Morphine derivatives with analgesic activity

ABSTRACT

Morphine derivatives of formula (I), process for perparing them and their use and use as analgesics. ##STR1##

The present invention relates to new improved morphine derivatives,processes for preparing them and their use as analgesics for treatingpain.

TECHNOLOGICAL BACKGROUND

Opiates are most commonly used as analgesics for treating severe chronicand acute pain. The opiate most frequently used at present for treatingsevere chronic or acute pain is morphine. An example of chronic pain isthe pain which occurs in cancer. An example of acute pain is the painwhich may occur after operations. The opiates used up until now fortreating such pain are indeed highly effective but have a number ofunpleasant and/or undesirable side effects, e.g. a short duration ofactivity, respiratory depression, nausea, constipation, diuresis andeuphoria and they are also addictive.

Morphine hydrazone derivatives with analgesic activity are known fromEP-A-0 242 417. EP-A-0 577 847 discloses 6-N-substituted morphinederivatives with analgesic and diuretic activity. EP-A-0 632 041discloses 6-nicotinoylaminomorphine derivatives having analgesicactivity.

A number of publications disclose preparations which attempt to avoidsome of the known disadvantages of the opiates used up until now.EP-B-300 806 discloses the use of phospholipid vesicles forencapsulating opioid analgesics. EP-A-672 416, EP-A-647 448, EP-A-631781 and WO 94/22431 disclose long-acting formulations of opiates in ahydrophobic matrix. All the formulations mentioned above have a durationof activity of from 12 to 24 hours. The disadvantages of thesepreparations are the delayed start of activity and the side effects,which still occur.

OBJECTIVE

There is therefore a need for compounds with powerful analgesic activitywhich can be taken orally, have a reduced side effects profile andwherein the analgesic activity starts quickly and is maintainedthroughout the desired period.

The object of the invention was therefore to provide new analgesicallyactive compounds which, compared with known opiates, especiallymorphine, are more effective when administered orally and parenterally,begin their analgesic effect more rapidly, continue to act for thedesired length of time and show a significant reduction in the typicalside effects.

This object has been achieved by means of the new morphine derivativesof formula I.

DESCRIPTION OF THE INVENTION

The invention therefore relates to morphine derivatives (these compoundsare referred to in the STN databases as morphians and this nomenclatureis used in the claims) of the formula ##STR2## wherein D denotes astraight-chained or branched, optionally halogenated C₁₋₄ -alkyl group,

the dotted line may represent a chemical bond, i.e. indicates that thecompounds are morphine derivatives or 7,8-dihydromorphine derivatives,

P denotes a group --C(L) (R₁) (R₂), --CO--C(L) (R₁) (R₂), --CO--N(L₁)(L₂) or --L₃

L denotes a group --A₁ --(C(R₃) (R₄))_(k) --A₂ --B or --A₁ --Q--A₂ --B

L₁ denotes a group --C(R₁) (R₂)--B, C(R₁) (R₂)--C(R₃) (R₄)--B or --R₁,

L₂ denotes a group --C(R₁) (R₂)--B or --C(R₁) (R₂)--C(R₃) (R₄)--B

L₃ denotes a group --Q--A₁ --B

k is an integer from 0 to 5

R₁, R₂, R₃ and R₄ independently of one another denote hydrogen, astraight-chained or branched, saturated or unsaturated C₁₋₄ -alkyl groupor a group --(CH₂)_(x) --OR₇, --(CH₂)_(x) --OC(O)R₇, (CH₂)_(x) --F,(CH₂)_(x) --Cl, (CHF)_(x) --F, (CHCl)_(x) --Cl, (CF₂)_(x) --F,(CCl₂)_(x) --Cl

x is an integer from 0 to 2,

A₁ and A₂ independently of each other denote a group --(CH₂)_(m) --,

m is an integer from 0 to 4

Q denotes a carbo- or heterocyclic, saturated, wholly or partiallyunsaturated, mono- or bicyclic 5-10-membered ring system, substituted byR³ and/or R⁴, with the exception of 7, 8, 9 and 10-membered monocyclicgroups,

B is a group X, CH(X) (Y) or C(X) (Y) (Z)

X, Y, Z independently of one another denote a group --(CH₂)_(n) --OH,--(CH₂)_(n) --CO₂ R₇, --(CH₂)_(n) --CN, --(CH₂)_(n) --CONR₅ OR₆,--(CH₂)_(n) CONR₅ R₆, --(CH₂)_(n) --OR₅, --(CH₂)_(n) --COR₅, --(CH₂)_(n)--OC(O)R₇, --(CH₂)_(n) --CONR₅ OR₆, --(CH₂ O_(n) --NR₅ C(O)R₆,--(CH₂)_(n) --SR₅, --(CH₂)_(n) S(O)R₅, --(CH₂)_(n) --S(O)₂ NR₅ R₆,--(CH₂)_(n) --NR₅ R₆, --(CH₂)_(n) --NHC(O)R₅, --(CH₂)_(n) --NHS(O)₂ R₅,--(CH₂)_(n) --F, --(CH₂)_(n) --Cl, --(CH₂)_(n) Br, --(CH₂)_(n) --NO₂

n is an integer from 0 to 4,

R₅, R₆ and R₇ independently of one another denote hydrogen or astraight-chained or branched C₁₋₄ -alkyl group, a C₁₋₄ -alkenyl group oran aryl or benzyl group, and the pharmaceutically acceptable saltsthereof.

DETAILED DESCRIPTION OF THE INVENTION

In formula I, D denotes a straight-chained or branched C₁₋₄ -alkyl groupwhich may optionally be substituted by halogen, such as Cl, F or Br.Examples of such groups include methyl, ethyl, propyl, i-propyl, butyl,i-butyl or t-butyl, trifluoromethyl, chloromethyl, bromoethyl,dibromoethyl and the like.

A₁ and A₂ independently of each other denote a group --(CH₂)_(m) -- andm is an integer from 0 to 4. Examples of such groups are methylene,ethylene, propylidene and butylidene groups. A₁ and/or A₂ may alsorepresent a bond.

Q denotes a carbo- or heterocyclic, saturated, wholly or partiallyunsaturated, mono- or bicyclic 5-10-membered ring system substituted byR³ and/or R⁴, with the exception of 7, 8, 9 and 10-membered monocyclicgroups.

Examples of such ring systems are cyclopentyl, cyclopentenyl,cyclopentadienyl, cyclohexyl, cyclohexenyl, tetrahydrofuryl, thiolanyl,pyrrolidinyl, dihydrofuryl, dihydrothienyl, dihydropyrrolyl,dihydrooxazolyl, dihydrothiazolyl, dihydropyrazolyl, furyl, thienyl,pyrrolyl, tetrahydropyranyl, thianyl, piperidinyl, dioxanyl,morpholinyl, piperazinyl, dihydropyranyl, tetrahydropyridinyl,isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, pyrazolyl, imidazolyl,triazolyl, pyranyl, cyclohexadienyl, phenyl, thiopyranyl,dihydropyridinyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl,oxadiazolyl, tetrazolyl, triazinyl, benzo[b]thienyl, benzofuryl,phthalimido, isobenzofuryl, indazolyl, quinolizinyl, quinolinyl orisoquinolinyl.

B denotes a group X, CH(X) (Y) or C(X) (Y) (Z), wherein X, Y, Zindependently of one another denote a group --(CH₂)_(n) --OH,--(CH₂)_(n) --CO₂ R₇, --(CH₂)_(n) --CN, --(CH₂)_(n) --CONR₅ OR₆,--(CH₂)_(n) --CONR₅ R₆, --(CH₂)_(n) --COR₅, --(CH₂)_(n) --COR₅,--(CH₂)_(n) --OC(O)R₇, --(CH₂)_(n) --CONR₅ OR₆, --(CH₂)_(n) --NR₅C(O)R₆, --(CH₂)_(n) --SR₅, --(CH₂)_(n) --S(O)R₅, --(CH₂)_(n) --S(O)₂ R₅,--(CH₂)_(n) --S(O)₂ NR₅ R₆, --(CH₂)_(n) --NR₅ R₆, --(CH₂)_(n) --NO₂ andn denotes an integer from 0 to 4.

Examples of such groups are polar groups, e.g. hydroxy, halogen,carboxy, cyano, carbamoyl, alkoxy, alkyloxy, alkylthio,(alkyl)oxysulphenyl, (alkyl)oxysulphynyl, sulphamoyl, amino groups oralkyl groups substituted by these groups, such as substituted methyl,ethyl, propyl and butyl groups.

R₁, R₂, R₃ and R₄ independently of one another denote hydrogen, astraight-chained or branched, saturated or unsaturated C₁₋₄ -alkyl groupor a group --(CH₂)_(x) --OR₇, --(CH₂)_(x) --OC(O)R₇, (CH₂)_(x) --F,(CH₂)_(x) --Cl, (CHF)_(x) --F, (CHCl)_(x) --Cl, (CF₂)_(x) --F,(CCl₂)_(x) --Cl, wherein x is an integer from 0 to 2.

Examples of such groups are methyl, ethyl, propyl, isopropyl, butyl,isobutyl or tert.-butyl, ethenyl, propenyl, butenyl or hydroxyalkylgroups such as hydroxymethyl, hydroxyethyl or mono- or poly-halogenatedmethyl or ethyl groups, such as mono-, di- or trifluoromethyl, mono-,di-, trichloromethyl, mono-, di- or trichloroethyl, mono-, di-, tri- orpentafluoroethyl and the like.

R₅, R₆ and R₇ independently of one another denote hydrogen or astraight-chained or branched C₁₋₄ -alkyl group, e.g. methyl, ethyl,propyl, isopropyl, butyl, isobutyl or tert.-butyl, an alkenyl group,such as ethenyl, propenyl, an aryl group or a benzyl group.

The compounds of general formula I according to the invention or thepharmaceutically acceptable salts thereof are powerful analgesics, bothorally and parenterally. Compared with known opiates, they have asignificantly better profile of side effects, namely reduced respiratorydepression, less tendency to constipation, reduced nausea and lesstendency to habituation (a lower addictive potential) in relation to theeffective dose. These properties of the new morphine derivatives arebased on their structure and their advantageous receptor andsub-receptor profile. Receptors, particularly opiate receptors, andtheir sub-receptors are discussed in the following publications, forexample:

Handbook of Experimental Pharmacology 104/1+2, Opioids I+II, A. Herz, H.Akil, E. J. Simon Ed., Springer Verlag, Berlin 1993.

A wide therapeutic window is opened up by the pharmacological propertiesdescribed above. The new compounds can therefore be used on their own orin conjunction with other active substances in the form of aconventional galenic preparation, as a therapeutic agent for thetreatment and alleviation of pain.

The invention therefore also relates to pharmaceutical preparationswhich contain the compounds of formula I according to the invention orthe salts thereof, on their own or in admixture with othertherapeutically useful active substances, as well as conventionalgalenic excipients and/or carriers or diluents. The compounds of formulaI may be administered orally in the form of tablets or capsules whichcontain a dosage unit of the compound together with excipients anddiluents such as maize starch, calcium carbonate, dicalcium phosphate,alginic acid, lactose, magnesium stearate, primogel or talc. The tabletsare produced in the conventional way by granulating the ingredients andcompressing them whilst capsules are produced by packing the contentsinto hard gelatine capsules of a suitable size. The compounds accordingto the invention may also be administered in the form of suppositorieswhich contain excipients such as beeswax derivatives, polyethyleneglycolor polyethyleneglycol derivatives, linolyic or linolenic acid esters,together with a dosage unit of the compound, and these are administeredrectally.

The compounds according to the invention may also be administered byparenteral route, for example by intramuscular, intravenous orsubcutaneous injection or by direct injection to the central nervoussystem, e.g. intrathecally. For parenteral administration they are bestused in the form of a sterile aqueous solution which may contain otherdissolved substances such as tonic agents, agents for adjusting the pH,preservatives and stabilisers. The compounds may be added to distilledwater and the pH can be adjusted to 3 to 6 using citric acid, lacticacid or hydrochloric acid, for example. Sufficient dissolved substancessuch as dextrose or saline solution may be added to make the solutionisotonic. Furthermore, preservatives such as p-hydroxybenzoates andstabilisers such as EDTA may be added to ensure that the solution issufficiently durable and stable. The resulting solution can then besterilised and transferred into sterile glass ampoules of theappropriate size to contain the desired volume of solution. Thecompounds according to the invention may also be administered byinfusion of a parenteral formulation as described above.

The compounds according to the invention may also be administered in theform of an oily preparation, a buffered or unbuffered emulsion, a gel ora cream, by means of a transdermal plaster.

For oral administration in humans, it is assumed that the daily dosewill be in the range from 0.001 to 5000 mg per day for a typical adultpatient weighing 70 kg. Therefore, tablets or capsules may generallycontain 0.0003 to 2000 mg of active compound, e.g. 0.01 to 500 mg, fororal administration up to three times a day. For parenteraladministration, the dose may be in the range from 0.001 to 5000 mg per70 kg per day, for example about 0.5 mg to 2500 mg.

In view of the pharmacological properties of the compounds according tothe invention, the invention also relates to a method of treating pain,preferably post-operative or chronic pain, characterised in that atherapeutically effective quantity of a pharmaceutical composition asdescribed above is administered to a patient.

PROCESS FOR PREPARATION

The invention also relates to the processes by which the compounds offormula I according to the invention may be prepared.

Ethers, i.e. compounds in which P is --C(L) (R₁) (R₂) or --L₃, can beprepared as follows: ##STR3## Morphine (1) is selectively protected inthe 3-position with chloromethylmethylether (2) in a suitable solvent(such as methanol) using a strong base (such as Na methoxide).Etherification is carried out according to step b with a suitablehalogenated substrate (4a, 4b, 4c), after first forming the 6-alkoxidewith NaH, in a suitable aprotic solvent (such as DMF). The protectinggroup is cleaved under conventional acidic conditions (e.g. glacialacetic acid) to obtain the desired product (6) as an acid addition salt.If desired, the free compound may be prepared by reacting with asuitable base (such as NaOH).

Esters, i.e. compounds in which P is --CO--C(L) (R₁) (R₂), can beprepared as follows: ##STR4## Morphine (1) is selectively protected inthe 3-position with chloromethylmethylether (2) in a suitable solvent(such as methanol) using a strong base (such as Na-methoxide).Esterification is carried out according to process step b with asuitable carboxylic acid (4a) or with a suitable carboxylic acidderivative (4b, c) using suitable activating agents such asN,N'-dichlorohexyl-carbodiimide and 4-dimethylaminopyridine in asuitable solvent (such as CH₂ Cl₂). If desired, the protective group iscleaved under conventional acidic conditions (e.g. glacial acetic acid),to obtain the desired product (6) in the form of an acid addition salt.If desired, the free compound may be prepared by reacting with asuitable base (such as NaOH).

Carbamates, i.e. compounds in which P is --CO--N(L₁) (L₂), can beprepared as follows: ##STR5## Morphine (1) is selectively protected inthe 3-position with chloromethylmethylether (2) in a suitable solvent(such as methanol) using a strong base (such as Na-methoxide). Theprotected morphine derivative (3) thus obtained is then reacted in stepb with an isocyanato derivative in the presence of a suitable reducingagent (such as NaH) and a suitable solvent (such as DMF) to obtain theprotected product (4). In step c the protecting group is cleaved underconventional acidic conditions (e.g. glacial acetic acid), to obtain thedesired product (5) as an acid addition salt. If desired, the freecompound may be prepared by reacting with a suitable base such as NaOH.

In all cases 7,8-dihydromorphine compounds may be prepared byhydrogenation prior to the final step of cleaving the 3-positionprotecting group. The protected morphine compound is hydrogenated usinga suitable catalyst, such as Pd on charcoal, in the presence of asolvent which is inert under the reaction conditions, such as a loweralcohol, e.g. methanol or ethanol.

The bases of formula I may be converted into their pharmaceuticallyacceptable salts with organic or inorganic acids in the usual way. Saltformation may be carried out, for example, by dissolving a compound offormula I in a suitable solvent such as water, acetone, acetonitrile,benzene, dimethylformamide, dimethylsulphoxide, chloroform, dioxane,methanol, ethanol, hexanol, ethyl acetate or in an aliphatic ether, suchas diethylether, or mixtures of such solvents, adding an at leastequivalent quantity of the desired acid, ensuring thorough mixing and,once the salt formation has ended, filtering off the precipitated salt,lyophilising it or distilling off the solvent in vacuo. If desired, thesalts may be recrystallised after isolation or their solutions may belyophilised.

Pharmaceutically acceptable salts are those with inorganic acids such ashydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid ornitric acid, or those with organic acids such as citric acid, tartaricacid, maleic acid, fumaric acid, succinic acid, malic acid,methanesulphonic acid, aminosulphonic acid, acetic acid, benzoic acidand the like.

PHARMACOLOGICAL INVESTIGATIONS

METHOD: Haffner Test ("Tail clip test") in Mice

The Haffner test is a standard procedure for determining thepain-inhibiting effect of powerful analgesics, mostly of the opioidtype, in mice. The method largely corresponds to the one described byBianchi C. and Franceschini J. (Brit. J. Pharmacol. 9:280, 1954;Experimental observations on Haffner's method for testing analgesicdrugs).

Male CD mice (from Charles River, Sulzfeld, FRG) with an average weightof 30±5 grams were used. The animals were kept under standard conditions(temperature: 22±2° C., relative humidity: 55±10%, air exchange: 15-20times per hour and 12/12 hours light/darkness cycle). The animals hadunlimited access to food and water until the test began. During the testthe animals were kept singly in Makrolon Type III cages with no bedding.A 3.5 cm arterial clamp was placed about 2 cm from the base of the tailand the pain reaction time was measured in seconds. Any active attemptby the animal to remove the clamp was assessed as a pain reaction. Toprevent tissue damage, the test was stopped after at most 30 seconds inevery case (cut off latency). In a preliminary test, mice with a painreaction time of less than 5 seconds (base line latency) were selectedfor the actual test, which was carried out at specific intervals afterthe administration of the drug (test latency).

Corresponding quantities of test substances were dissolved inphysiological saline solution for intravenous administration or in twicedistilled water for oral administration. The total volume administeredwas 10 ml/kg of body weight in each case. Controls were given the samesolvent but with no test substance. 8-10 mice were tested in each group.

The results were plotted as individual values (seconds), meanvalue±scattering (seconds) per group and as the percent of the maximumpossible effect (% MPE=percent of Maximum Possible Effect). ##EQU1##Significant differences between the control and test groups werecalculated by means of an unpaired, two-sided Students T-test (*2P<0.05;**2P<0.01; 2P<0.001).

The ED₅₀ value describes the dosage at which 50% of the maximum possibleeffect (MPE) is achieved. The ED₅₀ value is calculated by linearregression between the dose and the % MPE.

1) ETHERS EXAMPLE 16α-((4-Acetyloxy-butyl)-oxy)-4,5α-epoxy-17-methyl-morphinan-7-en-3-olacetate

6α-((4-Acetyloxy-butyl)-oxy)-4,5α-epoxy-3-methoxymethoxy-morphinan-7-ene(133 mg, 0.3 mmol) is dissolved in water (4,5 ml) and glacial aceticacid (4,5 ml) and then stirred for 6 hours at 100° C. The volatilecomponents are eliminated using the Rotavapor. The residue thus obtainedis purified by flash chromatography (10 g silica gel; mobile phase:methylene chloride/methanol=9:1).

Yield: 100 mg6α-((4-acetyloxy-butyl)-oxy)-4,5α-epoxy-17-methyl-morphinan-7-en-3-ol(0.22 mmol, 73%).

¹³ C NMR (100 MHz, CDCl₃) δ 176.4, 171.6, 146.3, 139.1, 131.4, 129.4,126.9, 123.1, 119.3, 117.5, 89.2, 74.3, 68.6, 59.0, 46.3, 42.6, 41.4,38.7, 33.8, 25.9, 25.3, 22.3, 21.4, 20.9;

The starting compound is prepared as follows:

4,5α-Epoxy-3-methoxymethoxy-17-methyl-morphinan-7-en-6α-ol

Morphine (36.4 g, 120 mmol) is dissolved in absolute methanol withstirring (700 ml). A 29.7% sodium ethoxide solution in methanol (116.4g, 640 mmol) is added dropwise to this solution. The resulting mixtureis cooled to 0° C. and within 10 minutes chloromethyl-methylether (48.6ml, 640 mmol) is added dropwise, during which time a white precipitateis formed and a temperature rise of about 5° C. is observed. Thereaction mixture is poured onto water (1200 ml) and the mixture isextracted 3× with dichloromethane. The combined organic phase is dried(Na₂ SO₄) and evaporated down using a Rotavapor. The product is driedfor a further 4 hours at 0.01 Torr.

Yield of 4,5α-epoxy-3-methoxymethoxy-17-methyl-morphinan-7-en-6α-ol34.25 g (86.7%).

¹³ C NMR (CDCl₃) δ 146.7, 138.3, 133.8, 132.0, 128.8, 127.9, 120.1,118.5, 95.5, 91.3, 66.0, 58.9, 56.1, 46.4, 43.0, 42.5, 40.6, 35.5, 20.5;

6α-((4-Acetyloxy-butyl)-oxy)-4,5α-epoxy-3-methoxymethoxy-17-methyl-morphinan-7-ene

NaH (50% suspension in mineral oil, 648 mg, 13.5 mmol) is washed 3× withn-pentane (8 ml) and stirred with absolute dimethylformamide at ambienttemperature. Then a solution of4,5α-epoxy-3-methoxymethoxy-17-methyl-morphinan-7-en-6α-ol (2.97 g, 9mmol) in dimethylformamide is added. After the development of gas hasceased, a solution of 4-iodo-butylacetate (7.62 g, 31.5 ml) indimethylformamide (12 ml) is added. The resulting mixture is stirred fora further 2 hours at ambient temperature, the reaction mixture is pouredonto water (150 ml) and extracted 3× with methylene chloride. Themethylene chloride phases are combined, dried over Na2SO4, filtered andconcentrated by rotary evaporation. The residue thus formed is purifiedby flash chromatography (90 g silica gel; mobile phase: methylenechloride/methanol=9:1). Yield: 2.47 g6α-((4-acetyloxybutyl)-oxy)-4,5α-epoxy-3-methoxymethoxy-17-methyl-morphinan-7-ene(5.58 mmol, 62%).

¹³ C NMR (CDCl₃) δ 171.0, 148.6, 138.8, 131.2, 130.8, 128.7, 128.5,118.9, 118.3, 96.0, 89.7, 74.4, 68.3, 64.2, 58.8, 56.1, 46.4, 43.2,43.0, 41.1, 35.8, 26.3, 25.4, 20.8, 20.5;

EXAMPLE 24,5α-Epoxy-6α((4-hydroxy-butyl)-oxy)-17-methyl-morphinan-7-en-3-olacetate

Aqueous 1 M NaOH (0.87 ml, 0.87 mmol) is added to a solution of6α-((4-acetyloxy-butyl)-4,5α-epoxy-17-methyl-morphinan-7-en-3-ol (100mg, 0.218 mmol) in water (2 ml). After 15 minutes at ambient temperaturethe solution is concentrated in a Rotavapor. The residue thus formed isdissolved in a mixture of water (0.3 ml) and glacial acetic acid andlyophilised.

Yield: 75 mg (0.21 mmol, 82%)4,5α-epoxy-6α-((4-hydroxy-butyl)-oxy)-17-methyl-morphinan-7-en-3-olacetate

¹³ C NMR (CDCl₃) δ 175.6, 146.1, 139.2, 130.0, 129.5, 128.4, 124.7,120.1, 119.0, 89.0, 74.0, 69.6, 63.1, 59.0, 46.3, 42.5, 42.2, 39.6,34.4, 31.0, 28.9, 21.8, 20.9.

The following were prepared analogously to Example 1 or 2

EXAMPLE 36α-((4-benzoyloxy-butyl)oxy)-4,5α-epoxy-3-methoxymethoxy-17-methyl-morphinan-7-ene

ES MS m/z 506 (M+H⁺)

EXAMPLE 46α-((4-benzoyloxy-butyl)-oxy)-4,5α-epoxy-17-methyl-morphinan-7-en-3-olacetate

¹³ C NMR (100 MHz, CDCl₃) δ 176.2, 167.5, 146.5, 139.4, 133.3, 132.3,130.6, 129.9, 129.4, 128.7, 126.4, 119.9, 118.0, 89.5, 69.0, 65.4, 60.2,47.1, 42.8, 42.1, 38.9, 33.7, 26.4, 25.8, 22.3, 22.0, 20.1.

EXAMPLE 54,5α-Epoxy-3-methoxymethoxy-17-methyl-6α-((4-pivaloyloxy-butyl)-oxy)-morphinan-7-ene

¹³ C NMR (100 MHz, CDCl₃) δ 178.4, 148.7, 139.4, 132.1, 130.2, 126.4,126.2, 119.2, 119.0, 96.0, 89.1, 73.9, 68.7, 64.1, 59.9, 56.2, 46.9,42.4, 39.3, 38.6, 36.3, 34.1, 27.1, 26.4, 25.4, 21.5.

EXAMPLE 64,5α-Epoxy-17-methyl-6α-((4-pivaloyloxy-butyl)-oxy)-morphinan-7-en-3-olacetate

¹³ C NMR (100 MHz, CDCl₃) δ 179.2, 176.1, 146.3, 138.8, 131.2, 129.7,127.4, 124.0, 119.4, 117.3, 89.6, 74.6, 68.6, 64.3, 59.0, 46.3, 43.0,41.8, 39.4, 38.8, 34.4, 27.2, 25.9, 25.5, 22.1, 21.2.

EXAMPLE 76α-((5-Acetyloxy-pentyl)-oxy)-4,5α-epoxy-3-methoxymethoxy-17-methyl-morphinan-7-ene

¹³ C NMR (100 MHz, CDCl₃) δ 171.2, 148.8, 139.5, 132.2, 130.6, 126.9,126.8, 119.4, 119.1, 96.2, 89.4, 74.2, 69.2, 64.6, 59.9, 56.4, 47.0,42.7, 42.6, 39.6, 34.5, 29.8, 29.3, 28.5, 22.7, 21.6, 21.1.

EXAMPLE 86α-((5-Acetyloxy-pentyl)-oxy)-4,5α-epoxy-17-methyl-morphinan-7-en-3-olacetate

¹³ C NMR (100 MHz, CDCl₃) δ 175.8, 171.3, 146.3, 139.3, 131.9, 128.7,125.8, 121.8, 119.6, 118.1, 88.9, 74.0, 69.5, 64.3, 60.0, 50.2, 46.8,42.2, 41.3, 38.0, 32.8, 29.1, 28.2, 22.4, 21.8, 20.8.

EXAMPLE 94,5α-Epoxy-3-methoxymethoxy-6α-((5-hydroxypentyl)-oxy)-17-methyl-morphinan-7-ene

¹³ C NMR (100 MHz, CDCl₃) δ 147.9, 138.3, 130.9, 130.0, 126.6, 126.58,118.6, 118.2, 95.4, 88.8, 73.5, 68.6, 61.6, 58.8, 55.6, 49.4, 46.0,42.1, 41.9, 39.0, 33.8, 31.7, 28.8, 21.7.

EXAMPLE 104,5α-Epoxy-6α-(5-hydroxypentyl)-oxy)-17-methyl-morphinan-7-en-3-olacetate

¹³ C NMR (100 MHz, D₂ O) δ 184.0, 148.5, 140.9, 132.1, 129.0, 126.3,122.9, 120.4, 91.4, 76.2, 72.5, 64.3, 62.9, 49.6, 43.4, 40.3, 34.7,33.7, 31.2, 26.0, 24.3;

EXAMPLE 114,5α-Epoxy-6α-((3-ethoxycarbonyl-(E)-prop-2-enyl)-3-methoxymethoxy-17-methyl-morphinan-7-ene

¹³ C NMR (100 MHz, d₆ -DMSO) δ 164.6, 148.3, 138.8, 135.2, 134.0, 130.6,130.1, 125.4, 125.0, 119.4, 119.1, 95.4, 91.4, 66.2, 65.7, 60.7, 59.7,55.9, 55.4, 50.8, 41.2, 32.8, 29.1, 23.5, 14.2.

EXAMPLE 124,5α-Epoxy-6α-(3-ethyloxycarbonyl-(E)-prop-2-enyl)-17-methyl-morphinan-7-en-3-olacetate

³ C NMR (100 MHz, D₂ O) δ 168.2, 146.9, 139.8, 135.1, 133.9, 133.4,130.7, 126.8, 124.3, 121.9, 119.5, 91.7, 68.7, 67.1, 64.0, 62.0, 57.6,52.7, 43.0, 42.9, 34.6, 30.8, 25.0, 24.8, 15.0.

EXAMPLE 136α-((N,N-Diethylcarbamoyl-methyl)-oxy)-4,5α-epoxy-3-methoxymethoxy-17-methyl-morphinan-7-ene

¹³ C NMR (100 MHz, CDCl₃) δ 167.4, 147.6, 138.0, 130.3, 129.4, 127.9,127.8, 118.1, 117.2, 95.1, 88.5, 73.5, 67.6, 58.0, 55.3, 45.5, 42.4,42.1, 40.5, 40.0, 39.0, 34.8, 19.7, 13.3, 11.8.

EXAMPLE 146α-((N,N-Diethylcarbamoyl-methyl)-oxy)-4,5α-epoxy-17-methyl-morphinan-7-en-3-olacetate

¹³ C NMR (100 MHz, CDCl₃) δ 176.6, 169.1, 146.5, 139.7, 130.6, 129.9,128.3, 123.9, 119.9, 118.2, 89.6, 74.0, 68.4, 59.4, 46.7, 42.7, 42.0,41.8, 40.6, 39.2, 34.2, 22.6, 21.5, 14.5, 13.0.

EXAMPLE 156α-((N,N-Dimethylcarbamoyl-methyl)-oxy)-4,5α-epoxy-3-methoxymethoxy-17-methyl-morphinan-7-ene

¹³ C NMR (100 MHz, CDCl₃) δ 169.1, 148.4, 138.9, 131.1, 130.2, 128.8,128.7, 119.0, 118.0, 95.9, 89.3, 74.4, 68.5, 58.8, 56.1, 46.4, 43.2,42.9, 40.8, 36.6, 35.6, 35.5, 20.6.

EXAMPLE 166α-((N,N-Diethylcarbamoyl-methyl)-oxy)-4,5α-epoxy-17-methyl-morphinan-7-en-3-olacetate

¹³ C NMR (100 MHz, CDCl₃) δ 176.1, 169.6, 146.1, 139.5, 130.6, 129.3,127.5, 122.9, 119.8, 118.3, 89.3, 73.5, 68.0, 59.2, 46.4, 42.1, 41.3,38.3, 36.7, 35.7, 33.3, 21.9, 21.4.

EXAMPLE 176α-(((4S)-2,2-Dimethyl-1,3-dioxolan-4-yl)-methyloxy)-4,5α-epoxy-3-methoxymethoxy-17-methyl-morphinan-7-ene

³ C NMR (100 MHz, CDCl₃) δ 148.6, 138.9, 130.6, 128.73, 128.71, 119.1,118.4, 109.2, 96.1, 89.7, 74.9, 69.4, 66.8, 58.9, 56.3, 46.5, 43.3,43.1, 41.1, 35.9, 26.7, 25.5, 20.5.

EXAMPLE 186α-((2R)-2,3-Dihydroxy-propyloxy)-4,5α-epoxy-17-methyl-morphinan-7-en-3-olacetate

¹³ C NMR (100 MHz, D₂ O) δ 181.8, 148.3, 140.7, 133.7, 131.8, 128.6,126.0, 123.0, 120.5, 91.0, 76.6, 73.2, 73.1, 65.3, 63.3, 49.9, 44.3,43.6, 41.2, 35.2, 24.6, 23.6.

EXAMPLE 196α-(((4R)-2,2-Dimethyl-1,3-dioxolan-4-yl)-methyloxy)-4,5α-epoxy-3-methoxymethoxy-17-methyl-morphinan-7-ene

¹³ C NMR (100 MHz, CDCl₃) δ 148.6, 138.9, 131.3, 130.6, 128.73, 128.71,119.1, 118.4, 109.2, 96.1, 89.7, 74.9, 69.4, 66.8, 58.9, 56.3, 46.5,43.3, 43.1, 41.1, 35.9, 26.7, 25.5, 20.5.

EXAMPLE 206α-((2S)-2,3-Dihydroxy-propyloxy)-4,5α-epoxy-17-methyl-morphinan-7-en-3-olacetate

¹³ C NMR (100 MHz, D₂ O) δ 181.2, 148.3, 140.7, 133.7, 131.8, 128.6,125.9, 123.0, 120.5, 91.0, 76.7, 73.3, 65.3, 63.3, 49.9, 44.3, 43.6,41.2, 35.3, 24.3, 23.6.

EXAMPLE 214,5-Epoxy-6α-(5-ethyloxycarbonyl-pentyloxy)-3-methoxymethoxy-17-methyl-morphinan-7-ene

¹³ C NMR (100 MHz, CDCl₃) δ 173.6, 162.4, 148.7, 139.1, 131.6, 130.8,127.5, 127.4, 119.0, 118.7, 96.0, 89.5, 74.2, 69.0, 60.1, 59.4, 56.2,46.7, 42.9 42.7, 40.2, 35.0, 34.2, 29.5, 25.7, 24.7, 21.0, 14.2.

EXAMPLE 224,5α-Epoxy-6α-(5-ethyloxycarbonyl-pentyloxy)-17-methyl-morphinan-7-en-3-olacetate

¹³ C NMR (100 MHz, CDCl₃) δ 174.5, 146.7, 139.1, 132.1, 129.8, 127.1,123.8, 119.8, 117.8, 89.9, 74.8, 69.6, 60.7, 60.0, 47.1, 43.2, 42.4,39.6, 34.6, 34.4, 29.6, 26.0, 24.8, 21.8, 14.5.

EXAMPLE 236α-((5-Carboxyl-pentyl)-oxy)-4,5α-epoxy-17-methyl-morphinan-7-en-3-olacetate

¹³ C NMR (100 MHz, d₆ -dmso) δ 174.9, 146.4, 138.5, 130.9, 130.7, 129.3,125.4, 118.4, 116.3, 88.9, 74.4, 68.3, 58.1, 46.1, 43.2, 42.8, 35.6,34.0, 29.3, 25.4, 24.6, 20.2.

EXAMPLE 244,5α-Epoxy-6α-((4-ethyloxycarbonyl-butyl)-oxy)-3-methoxymethoxy-17-methyl-morphinan-7-ene

¹³ C NMR (100 MHz, CDCl₃) δ 173.9, 149.0, 139.3, 131.6, 131.2, 128.2,128.1, 119.3, 118.9, 96.3, 89.8, 74.6, 68.9, 60.3, 59.5, 56.5, 46.9,43.3, 43.1, 40.8, 35.6, 34.2, 29.5, 21.9, 21.2, 14.4.

EXAMPLE 254,5α-Epoxy-6α-((4-ethyloxycarbonyl-butyl)-oxy)-17-methyl-morphinan-7-en-3-olacetate

¹³ C NMR (100 MHz, CDCl₃) δ 176.1, 174.3, 146.2, 139.1, 132.0, 129.2,126.2, 122.7, 119.5, 117.7,89.0, 74.0, 68.5, 60.5, 59.6, 46.6, 42.5,41.5, 38.5, 33.8, 33.5, 29.0, 22.0, 21.8, 21.6, 13.6.

EXAMPLE 264,5α-Epoxy-6α-(4-cyanobutyloxy)-3-methoxymethoxy-17-methyl-morphinan-7-ene

¹³ C NMR (100 MHz, CDCl₃) δ 148.7, 139.3, 131.3, 131.2, 128.52, 128.49,120.2, 129.3, 118.4, 96.2, 89.6, 74.5, 67.9, 59.3, 56.5, 46.8, 43.3,43.1, 40.9, 35.8, 28.9, 22.9, 21.0, 17.0.

EXAMPLE 27 4,5α-Epoxy-6α-(4-cyanobutyloxy)-17-methyl-morphinan-7-en-3-olacetate

¹³ C NMR (100 MHz, CDCl₃) δ 176.6, 146.6, 139.2, 131.6, 129.9, 127.4,123.9, 120.3, 119.8, 117.7,89.6, 74.6, 68.4, 59.5, 46.8, 43.0, 42.0,39.2, 34.2, 28.9, 22.8, 22.5, 21.7, 17.2.

EXAMPLE 284,5α-Epoxy-6α-((4-methoxycarbonyl-butyl)-oxy)-3-methoxymethoxy-17-methyl-morphinan-7-en

¹³ C NMR (100 MHz, CDCl₃) δ 173.9, 148.7, 138.9, 131.2, 1131.1, 128.3,128.1, 118.9, 118.5, 96.1, 89.6, 74.4, 68.5, 59.0, 56.2, 51.3, 46.5,43.1, 42.9, 40.8, 35.6, 33.7, 29.3, 21.7, 20.7.

EXAMPLE 294,5α-Epoxy-6α-((4-methoxycarbonyl-butyl)-oxy)-17-methyl-morphinan-7-en-3-olacetate

¹³ C NMR (100 MHz, CDCl₃) δ 176.4, 175.0, 146.6, 139.0, 131.7, 130.0,127.6, 124.4, 119.7, 117.6, 89.7, 74.6, 68.7, 59.5, 52.0, 46.8, 43.3,42.3, 39.8, 34.7, 33.9, 29.3, 22.5, 22.1, 21.5.

EXAMPLE 306α-((4-Carboxyl-butyl)-oxy)-4,5α-epoxy-17-methyl-morphinan-7-en-3-olacetate

¹³ C NMR (100 MHz, d₆ -dmso) δ 175.0, 146.4, 138.6, 130.7, 129.3, 125.3,118.5, 116.3, 88.9, 74.34, 68.1, 58.0, 48.7, 46.0, 43.1, 40.7, 35.6,34.1, 29.0, 21.6, 20.1.

EXAMPLE 316α-((2-Acetyloxy-pentyl)-oxy)-4,5α-epoxy-3-methoxymethoxy-17-methyl-morphinan-7-ene

¹³ C NMR (100 MHz, CDCl₃) δ 170.5, 148.6, 139.7, 132.8, 129.5, 124.9,124.5, 119.4, 95.9, 95.8, 88.7,88.6, 73.5, 70.6, 69, 60.5, 56.2, 47.2,42.0, 41.8, 38.0, 32.4, 25.7, 24.2, 22.1, 21.2, 19.8, 13.6.

EXAMPLE 326α-((2-Acetyloxy-pentyl)-oxy)-4,5α-epoxy-17-methyl-morphinan-7-en-3-olacetate

¹³ C NMR (100 MHz, CDCl₃) δ 175.7, 172.1, 146.5, 139.8, 133.0, 128.9,125.3, 121.6, 120.1, 118.4, 89.2, 74.2, 71.3, 71.0, 69.3, 68.9, 61.0,59.6, 47.6, 42.4, 42.0, 38.2, 32.9, 32.7, 25.8, 25.4, 24.6, 22.5, 21.8,21.7, 21.6, 20.3, 20.1, 14.0.

EXAMPLE 336α-((2-Hydroxypentyl)-oxy)-4,5α-epoxy-17-methyl-morphinan-7-en-3-olacetate

¹³ C NMR (100 MHz, D₂ O) δ 148.4, 140.7, 133.9, 13.9, 128.6, 126.0,123.0, 120.5, 91.2, 76.0, 72.5, 70.3, 63.3, 50.0, 44.3, 43.7, 41.3,37.1, 35.3, 27.8, 24.5, 23.6.

EXAMPLE 346α-((5-Acetyloxy-4-methyl-pentyl)-oxy)-4,5α-epoxy-3-methoxy-methoxy-17-methyl-morphinan-7-ene

¹³ C NMR (100 MHz, CDCl₃) δ 171.0, 162.4, 148.6, 139.6, 132.6, 129.8,125.4, 125.1, 119.3, 119.2, 95.9, 88.9, 73.7, 69.5, 69.4, 69.2, 60.3,56.2, 47.1, 42.1, 42.1, 38.5, 36.3, 33.3, 32.3, 31.3, 29.7, 29.7, 27.1,21.9, 20.8, 16.7.

EXAMPLE 356α-((5-Acetyloxy-4-methyl-pentyl)-oxy)-4,5α-epoxy-17-methyl-morphinan-7-en-3-olacetate

¹³ C NMR (100 MHz, CDCl₃) δ 175.3, 171.6, 171.5, 146.3, 139.1, 132.4,132.3, 128.8, 125.5, 125.4, 122.0, 121.9, 119.8, 118.0, 117.0, 89.3,89.2, 74.0, 70.0, 69.7, 69.4, 69.3, 60.4, 47.1, 42.3, 41.7, 38.2, 32.9,32.4, 32.2, 29.9, 29.6, 27.1, 26.9, 22.0, 21.4, 20.9, 16.8.

EXAMPLE 364,5α-Epoxy-6α-((5-hydroxy-4-methyl-pentyl)-oxy)-17-methyl-morphinan-7-en-3-olacetate

¹³ C NMR (100 MHz, d₆ -dmso) δ 172.2, 146.4, 139.1, 131.9, 129.5, 126.8,122.9, 119.0, 117.1, 88.2, 73.9, 69.0, 66.3, 59.3, 46.2, 42.2, 41.0,40.2, 40.0, 35.3, 29.5, 27.1, 21.1, 16.9.

EXAMPLE 376α-((3-Acetyloxy-propyl)-oxy)-4,5α-epoxy-3-methoxymethoxy-17-methyl-morphinan-7-ene

¹³ C NMR (100 MHz, d₆ -dmso) δ 170.7, 148.4, 138.7, 130.7, 128.3, 128.2,118.8, 118.2, 95.8, 89.3, 74.2, 68.0, 65.3, 61.5, 58.8, 56.0, 46.4,42.7, 40.6, 35.4, 29.0, 20.7, 20.5.

EXAMPLE 386α-((3-Acetyloxy-propyl)-oxy)-4,5α-epoxy-17-methyl-morphinan-7-en-3-olacetate

¹³ C NMR (100 MHz, CDCl₃) δ 176.0, 172.3, 146.1, 138.6, 131.0, 129.9,128.0, 124.7, 124.7, 119.4, 117.3, 89.0, 74.3, 73.8, 64.8, 61.7, 59.0,46.4, 43.1, 42.3, 40.1, 35.0, 29.2, 21.0, 20.9.

EXAMPLE 394,5α-Epoxy-6α-((3-hydroxypropyl)-oxy)-17-methyl-morphinan-7-en-3-olacetate

¹³ C NMR (100 MHz, d₆ -dmso) δ 176.2, 145.6, 139.0, 131.0, 129.6, 127.3,124.1, 119.9, 118.6, 88.3, 72.7, 67.7, 62.0, 59.1, 46.5, 42.0, 41.8,38.9, 34.2, 31.3, 22.2, 20.9.

EXAMPLE 406α-((6-Acetyloxy-hexyl)-oxy)-4,5α-epoxy-3-methoxymethoxy-17-methyl-morphinan-7-ene

¹³ C NMR (100 MHz, d₆ -dmso) δ 170.7, 148.4, 138.7, 130.7, 128.3, 128.2,118.8, 118.2, 95.8, 89.3, 74.2, 68.0, 65.3, 61.5, 58.8, 56.0, 46.4,42.7, 40.6, 35.4, 29.0, 20.7, 20.5.

EXAMPLE 416α-((6-Acetyloxy-hexyl)-oxy)-4,5α-epoxy-17-methyl-morphinan-7-en-3-olacetate

¹³ C NMR (100 MHz, CDCl₃) α 171.3, 146.4, 138.7, 138.6, 131.0, 129.8,127.7, 124.3, 119.4, 117.4, 114.6, 89.8, 74.7, 69.7, 64.4, 59.2, 46.5,43.1, 42.2, 39.8, 34.6, 29.6, 28.5, 25.7, 21.1. 20.9.

EXAMPLE 424,5α-Epoxy-17-methyl-6α-((6-hydroxy-hexyl)-oxy)-morphinan-7-en-3-olacetate

¹³ C NMR (100 MHz, CDCl₃) δ 146.3, 138.9, 130.7, 129.8, 128.0, 124.2,119.6, 117.9, 89.8, 75.0, 69.9, 62.4, 59.0, 46.3, 43.1, 42.1, 39.7,34.5, 31.7, 29.1, 24.7, 21.2.

EXAMPLE 436α[2'(2-Dimethyl-1,3-dioxolan-4-yl)ethyl)oxy-4,5α-epoxy-3-methoxymethoxy-17-methyl-morphin-7-ene

C₂₆ H₃₅ NO₆

MW: 457.57 gmol⁻¹

Diastereomeric mixture at 3'-C; ¹³ C-data for both isomers.

¹³ CNMR(100 MHz, CDCL₃) δ 162.5, 148.6, 148.5 138.9, 138.8, 131.2,130.8, 130.7, 128.7, 128.6, 128.5, 118.9, 118.2, 118.1, 108.2, 96.0,95.9, 89.6, 89.5, 74.6, 74.5, 74.2, 73.8, 69.8, 69.96, 65.8, 65.7, 58.8,56.2, 50.5, 46.4, 43.2, 43.0, 41.0, 35.8, 34.0, 26.9, 26.8, 25.7, 20.6.

EXAMPLE 446α-[3',4'-Dihydroxybutyl]oxy-4,5α-epoxy-17-methyl-morphin-7-en-3-olacetate

C₃₃ H₃₁ NO₇

MW: 433.51 gmol⁻¹

Diastereomeric mixture at 3'-C; ¹³ C-data for both isomers.

¹³ C NMR (100 MHz CDCl₃) δ 176.4, 145.9, 145.7, 139.2, 139.1, 131.2,130.8, 129.4, 129.3, 127.1, 126.6, 123.4, 123.0, 120.1, 119.9, 118.9,118.3,88.5, 88.1, 73.3, 72.9, 71.7, 70.0, 66.7, 66.5, 66.3, 65.4, 59.2,59.1, 46.5, 46.4, 41.9, 41.8, 41.4, 41.3, 38.3, 38.2, 33.5, 33.4, 33.1,33.0, 22.0, 21.3.

EXAMPLE 456α-[2'(2-Dimethyl-1,3-dioxolan-4(R)-yl)ethyl]oxy-4,5α-epoxy-17-methyl-morphin-7-ene

C₂₆ H₅₅ NO₆

MW: 457.51 gmol⁻¹

¹³ CNMR(100MHz, CDCl₃) δ 148.6, 138.9, 131.2, 130.9, 128.6, 128.5,119.0, 118.3, 108.4, 96.0, 89.6, 74.6, 73.8, 69.7, 65.7, 59.0, 56.2,46.5,43.2, 43.0, 41.0, 35.8, 34.1, 26.9, 25.7, 20.6.

EXAMPLE 466α-[(3'R)-3',4'-Dihydroxybutyl]oxy-4,5α-epoxy-17-methyl-morphin-7-en-3-olacetate

C₂₃ H₃₁ NO₇

MW: 433.51 gmol⁻¹

¹³ CNMR (100 MHz, CDCl₃) δ 176.5, 145.8, 138.9, 130.5, 129.7, 127.8,124.2, 120.0, 118.6, 88.3, 73.5, 71.6, 66.6, 6.3, 59.0, 46.4, 42.2,41.9, 39.1, 34.2, 33.2, 22.3, 21.0.

EXAMPLE 476α-[2'(2-Dimethyl-1,3-dioxolan-4(S)-yl)ethyl]oxy-4,5α-epoxy-17-methyl-morphin-7-ene

C₂₆ H₃₅ NO₆

MW: 457.51 gmol⁻¹

¹³ CNMR(100 MHz, CDCl₃) δ 148.5, 138.9, 131.2, 130.8, 128.6, 128.5,118.9, 118.1, 108.2, 96.0, 89.5, 74.5, 74.2, 69.7, 65.7, 58.8, 56.1,46.4, 43.2, 43.0, 41.0, 35.8, 34.0, 26.8, 25.7, 20.6.

EXAMPLE 486α-[(3'S)-3',4'-Dihydroxybutyl]oxy-4,5α-epoxy-17-methyl-morphin-7-en-3-olacetate

C₂₃ H₃₁ No₇

MW: 433.51 gmol⁻¹

¹³ CNMR(100 MHz, CDCl₃) δ 176.6, 145.7, 139.0, 130.9, 129.6, 127.1,123.7, 119.8, 118.0, 88.7, 73.0, 70.0, 66.5, 65.3, 59.1, 46.4,42.1,41.8, 38.7, 33.9, 33.1, 22.3, 21.1.

EXAMPLE 494,5α-Epoxy-6α-[(methoxycarbonyl)propyl]oxy-3-methoxymethoxy-17-methyl-morphin-7-ene

C₂₄ H₃₁ NO6

¹³ CNMR(100 MHz, CDCl₃) δ 174.2, 148.0, 138.9, 131.1, 129.5, 128.8,128.6, 119.3, 118.6, 96.1, 88.5, 68.3, 59.1, 56.3, 46.6, 43.0, 42.9,40.7, 35.4, 20.6, 12.9, 8.6, 8.5.

EXAMPLE 504,5α-Epoxy-6α-[(methoxycarbonyl)propyl]oxy-17-methyl-morphin-7-en-3-olacetate

C₂₄ H₃₁ NO₇

MW: 445.49 gmol⁻¹

¹³ CNMR(100 MHz, CDCl₃) δ 176.2, 174.2, 145.5, 138.6, 129.6, 129.0,128.3, 124.5, 119.7, 117.1, 88.2, 67.9, 59.0, 46.5, 42.5, 41.9, 39.1,34.1,22.1, 21.0, 12.8, 8.7.

EXAMPLE 516α-[3'-Acetoxy-propyl]oxy-4,5α-epoxy-3-methoxymethoxy-17-methyl-morphin-7-ene

C₂₄ H₃₁ NO₆

MW: 429.52 gmol⁻¹

¹³ CNMR(100 MHz, CDCl₃) δ 170.8, 148.5, 138.7, 131.0, 130.6, 128.5,128.4, 118.8, 118.2, 95.8, 89.4, 74.3, 65.4, 61.5, 58.7, 46.2, 43.1,42.8, 40.8, 35.6, 29.0, 20.7, 20.4.

EXAMPLE 526α-[3'-Acetoxy-propyl]oxy-4,5α-epoxy-17-methyl-morphin-7-en-3-ol acetate

C₂ H₃₁ NO₇

MW: 445.52 gmol⁻¹

¹³ CNMR(100 MHz, CDCl₃) δ 176.2, 172.4, 146.1, 139.0, 131.6, 129.4,126.9, 123.3, 119.5, 117.5, 88.6, 73.9, 64.7, 61.7, 59.1, 46.3, 42.6,41.5, 38.8, 34.0, 29.1, 22.1, 21.3, 21.0.

Example A:

                  TABLE 1                                                         ______________________________________                                        Haffner test in mice, % MPE, ED.sub.50 values, i.v.                             Compound                                                                      according to ED.sub.50 [nmol/kg]                                            Example     10 min. 30 min.   60 min.                                                                             120 min.                                  ______________________________________                                         1          1.1     3.9       4.6   13                                          22 3 3.7 10 12                                                                 4 0.4 3.1 11.9 21.7                                                           6 0.5 2.6 11.4 29                                                             2 0.35 3.8 13.4 41                                                           25 1.1 5.7 11.2 12.9                                                          27 5.9 7.3 15.4 38                                                            29 3.7 3.9 4.1 5.0                                                            32 1.0 3.0 9.9 24                                                             33 1.9 4.6 8.3 21                                                             38 0.3 1.9 3.6 79                                                             29 0.6 1.3 2.9 13.4                                                           Morphine.HCl 17 19 21 37                                                    ______________________________________                                    

                  TABLE 2                                                         ______________________________________                                        Haffner test in mice, ED.sub.50 values in nmol/kg, p.o.                                   ED.sub.50 [nmol/kg]                                               Compound    30 min. 60 min.   120 min.                                                                             180 min.                                 ______________________________________                                         1          30      35        37     46                                         22 55 90 96 86                                                                 4 35 46 58 69                                                                 6 58 108 120 132                                                              2 17 21 33 36                                                                25 20.1 28 31 37                                                              27 59 73 108 178                                                              29 70 85 96 131                                                               32 68 120 154 232                                                             33 29 37 51 69                                                                38 23 27 35 43                                                                39 27 35 149 283                                                              Morphine.HCl 279 296 539 718                                                ______________________________________                                    

2) 7,8-DIHYDROMORPHINE ETHERS EXAMPLE 16α-((4-Acetyloxy-butyl)-oxy)-4,5-epoxy-17-methyl-morphinan-3-ol acetate

6α-((4-Acetyloxy-butyl)-oxy)-4,5α-epoxy-17-methyl-morphinan-7-en-3-olacetate (0.288 g, 0.63 mmol) in MeOH (30 ml) mixed with 10% Pd on 0.2 g)and then agitated for 1 hour at RT under H₂ (1 bar over pressure). Thecatalyst is removed by filtering through a filter compound and thefiltrate is concentrated by rotary evaporation. The residue obtained ispurified by flash chromatography (20 g silica gel; mobile phase: CH₂ Cl₂/MeOH=9/1). The product is dissolved in glacial acetic acid andlyophilised.

Yield: 0.20 g (0.43 mmol, 68.8%)6α-((4-acetyloxy-butoxy)oxy)-4,5α-epoxy-17-methyl-morphinan-3-ol-acetate

¹³ C NMR (300 MHz, CDCl₃) δ 171.7, 145.9, 138.9, 127.9, 120.4, 119.2,118.1, 88.8, 74.3, 69.8, 64.7, 62.2, 48.3, 41.6, 40.6, 38.0, 33.6, 26.2,25.5, 24.7, 21.6, 21.1, 18.0.

Starting compound: see Example 1 of "Ethers" above.

The following compounds were prepared analogously to Example 1:

EXAMPLE 26α-[3-(Acetyloxy)propyl]oxy-4,5α-3-methoxymethoxy-17-methyl-morphine

C₂₄ H₃₃ NO₆

MW: 431.53 gmol⁻¹

¹³ C NMR (100 MHz, CDCl₃) δ 170.7, 147.9, 139.5, 123.0, 118.7, 118.6,95.6, 88.7, 74.1, 66.3, 61.4, 61.3, 56.2, 48.0, 41.2, 40.2, 38.5, 33.7,28.9, 25.3, 21.3, 20.7, 17.5.

EXAMPLE 3 6α-[3-(Acetyloxy)propyl]oxy-4,5α-epoxy-17-methyl-morphin-3-olacetate

C₂₄ H₃₃ NO₇

MW: 447.53 gmol⁻¹

¹³ C NMR (100 MHz, CDCl₃) δ 175.2, 17.7, 146.1, 138.9, 127.8, 120.5,119.0, 118.4, 88.3, 74.2, 66.0, 48.1, 41.2, 40.6, 37.8, 33.8, 28.9,24.8, 21.2, 21.0, 20.7, 17.9.

Example A

                  TABLE 1                                                         ______________________________________                                        Haffner test in mice, ED.sub.50 values in nmol/kg, i.v.                           Compound                                                                    according to ED.sub.50 [nmol/kg]                                            Example     10 min. 30 min.   60 min.                                                                             120 min.                                  ______________________________________                                        1           1.5     1.9       3.7   9.1                                         7,8-Dihydro- 16 23 32 130                                                     morphine                                                                      Morphine.HCl 17 19 21 37                                                    ______________________________________                                    

                  TABLE 2                                                         ______________________________________                                        Haffner test in mice, ED.sub.50 values in nmol/kg, p.o.                         Compound                                                                      according to ED.sub.50 [nmol/kg]                                            Example    30 min. 60 min.   120 min.                                                                             180 min.                                  ______________________________________                                        1          18      30        43     85                                          7,8-Dihydro- 177 195 250 481                                                  morphine                                                                      Morphine.HCl 279 296 539 718                                                ______________________________________                                    

3) ETHERS CONTAINING A CYCLIC GROUP EXAMPLE 14,5α-Epoxy-17-methyl-6α-((2-tetrahydropyranyl-methoxy)-morphinan-7-en-3-olacetate

4,5α-Epoxy-3-methoxymethoxy-17-methyl-morphinan-7-en-6α-ol

See Example 1 of "Ethers" above

4,5α-Epoxy-3-methoxymethoxy-17-methyl-6α-((2-tetrahydropyranyl)-methoxy)-morphinan-7-ene

NaH (50% suspension in mineral oil, 1.44 mg, 60 mmol) is washed 3× withn-pentane (8 ml) and stirred with absolute dimethylformamide (24 ml) atambient temperature. Then a solution of4,5α-epoxy-4-methoxy-methoxy-17-methyl-morphinan-7-en-6α-ol (3.95 g, 12mmol) in dimethylformamide (24 ml) is added. After the development ofgas has ceased, a solution of 2-(bromomethyl)-tetrahydropyran (10.64 g,60 mmol) in dimethylformamide (16 ml) is slowly added dropwise. Theresulting mixture is then stirred for 2 hours at ambient temperature.The reaction mixture is poured onto water (150 ml) and extracted 3× withmethylene chloride (80 ml). The methylene chloride phases are combined,dried over Na₂ SO₄, filtered and concentrated by rotary evaporation. Theresidue thus obtained is purified by flash chromatography (90 g silicagel; mobile phase: methylene chloride/methanol=9:1). Yield: 2.17 g4,5α-epoxy-3-methoxymethoxy-17-methyl-6α-((2-tetrahydropyranyl)-methoxy)-morphinan-7-ene(42.3%).

¹³ C NMR (100 MHz, CDCl₃) δ 148.6, 138.8, 131.0, 130.9, 128.3, 128.1,118.9, 118.3, 118.2, 96.1, 95.9, 89.9, 89.5, 77.0, 76.9, 74.8, 72.7,72.5, 68.3, 68.2, 58.8, 56.2, 46.3, 43.2, 42.8, 40.9, 40.7, 35.6, 28.4,28.3, 25.9, 23.0, 20.6.

4,5α-Epoxy-17-methyl-6α-((2-tetrahydropyranyl)-methoxy)-morphinan-7-en-3-olacetate

4,5α-Epoxy-3-methoxymethoxy-17-methyl-6α-((2-tetrahydropyranyl)-methoxy)-morphinan-7-ene(2.17 g, 5.08 mmol) is dissolved in water (65 ml) and glacial aceticacid (65 ml) and then stirred for 6 hours at 100° C. The volatilecomponents are eliminated using the Rotavapor. The residue thus obtainedis purified by flash chromatography (130 g of silica gel; mobile phase:methylene chloride/methanol=9:1). The product is dissolved in a mixtureof water and glacial acetic acid and lyophilised. Yield: 1.55 g4,5α-epoxy-17-methyl-6α-((2-tetrahydropyranyl)-methoxy)-morphinan-7-en-3-olacetate (68.8%).

¹³ C NMR (100 MHz, CDCl₃) δ 176.2, 146.4, 139.5, 139.4, 132.0, 131.8,129.1, 125.9, 125.5, 122.5, 122.4, 119.8, 119.7, 118.3, 118.0, 88.9,88.4, 77.7, 77.5, 73.5, 73.2, 72.8, 72.1, 69.6, 68.3, 59.8, 59.6, 47.0,46.7, 41.8, 41.2, 38.0, 37.8, 33.0, 28.1, 27.8, 25.7, 23.1, 23.0, 21.8,21.6, 21.5.

The following were prepared analogously to Example 1:

EXAMPLE 2

4,3α-Epoxy-3-methoxymethoxy-17-methyl-6α-(N-morpholinyl-carbonyl-methyl-oxy)-morphinan-7-ene

¹³ C NMR (100 MHz, CDCl₃) δ 167.5, 148.0, 138.7, 130.9, 129.8, 128.9,128.5, 119.0, 117.7, 95., 88.8, 74.5, 68.7, 66.7, 66.5, 58.6, 55.9,46.2, 43.0, 40.6, 35.5, 20.4.

EXAMPLE 34,5α-Epoxy-17-methyl-6α-(N-morpholinyl-carbonyl-methyl-oxy)-morphinan-7-en-3-olacetate

¹³ C NMR (100 MHz, CDCl₃) δ 176.5, 168.6, 146.3, 139.7, 130.6, 129.8,128.3, 123.7, 120.1, 118.2, 89.5, 74.0, 68.7, 67.2, 59.4, 46.7, 46.4,42.7, 42.6, 41.8, 39.0, 34.0, 22.4, 21.6.

EXAMPLE 44,5α-Epoxy-3-methoxymethoxy-17-methyl-6α-((4-(methyloxy-carbonyl)-phenyl)-methoxy)-morphinan-7-ene

¹³ C NMR (100 MHz, CDCl₃) δ 166.8, 148.5, 143.7, 139.0, 131.0, 130.7,129.6, 129.3, 128.2, 127.2, 119.2, 118.5, 96.0, 89.4, 73.6, 70.1, 59.1,56.2, 52.0, 46.5, 43.1, 42.9, 40.6, 35.4, 20.8.

EXAMPLE 54,5α-Epoxy-17-methyl-6α-((4-(methyloxycarbonyl)-phenyl)-methoxy)-morphinan-7-en-3-olacetate

¹³ C NMR (100 MHz, CDCl₃) δ 176.1, 166.9, 146.1, 138.8, 130.6, 129.8,129.7, 129.6, 127.4, 124.0, 119.7, 117.6, 89.5, 73.8, 70.7, 59.0, 52.1,46.3, 42.9, 41.7, 39.1, 34.0, 21.8, 21.3.

EXAMPLE 64,5α-Epoxy-3-methoxymethoxy-17-methyl-6α-((3-(N-phthalimido)-propyl)-oxy)-morphinan-7-ene

¹³ C NMR (100 MHz, CDCl₃) δ 168.2, 148.6, 138.7, 133.7, 132.1, 131.2,130.7, 128.6, 128.3, 123.0, 118.8, 118.3, 96.0, 89.5, 74.5, 66.6, 58.7,56.1, 46.3, 43.1, 42.9, 40.9, 35.7, 35.5, 28.8, 20.5.

EXAMPLE 74,5α-Epoxy-17-methyl-6α-((3-(N-phthalimido)-propyl)-oxy)-morphinan-7-en-3-olacetate

¹³ C NMR (100 MHz, CDCl₃) δ 176.3, 169.3, 146.8, 139.2, 134.3, 132.4,132.0, 131.4, 129.9, 127.3, 124.1, 123.7, 119.8, 118.0, 89.4, 75.3,67.1, 59.3, 46.6, 43.2, 42.0, 39.4, 36.3, 34.5, 28.9, 22.3, 21.6.

EXAMPLE 84,5α-Epoxy-3-methoxymethoxy-17-methyl-6α-((4-(N-phhalimido)-butyl)-oxy)-morphinan-7-ene

¹³ C NMR (100 MHz, CDCl₃) δ 169.5, 161.9, 147.5, 138.8, 132.0, 128.5,128.3, 126.0, 122.2, 119.0, 118.6, 95.0, 87.7, 72.5, 60.0, 55.37, 48.2,38.4, 36.7, 35.8, 34.3, 30.6, 26.2, 25 .1, 24.4, 23.4, 20.1.

EXAMPLE 9 4,5α-Epoxy-17-metheyl-6α-((4-(N-phthalimido)-butyl)-oxy)-morphinan-7-en-3-ol acetate

¹³ C NMR (100 MHz, CDCl₃) δ 168.5, 145.9, 138.3, 133.6, 131.8, 130.8,129.6, 127.4, 124.4, 123.0, 119.0, 116.8, 89.2, 74.4, 68.2, 58.6, 46.0,42.8, 41.8, 39.6, 37.4, 34.5, 29.4, 26.7, 24.7, 20.7.

EXAMPLE 10(5α,6α)-6-[(4-Cyanophenyl)methyl]oxy-7,8-didehydro-4,5-epoxy-17-methyl-morphinan-3-olacetate

C₃₇ H₂₈ N₂ O₅

MW: 460.53 gmol⁻¹

¹³ CNMR(100 MHz, CDCl₃) δ 176.0, 146.2, 143.6, 138.4, 132.1, 130.2,129.7, 129.3, 127.8, 125.5, 119.3, 118.7, 117.1, 111.3, 89.5, 74.3,70.0, 58.7, 46.3, 43.4, 42.6, 40.6, 35.4, 20.6, 20.2.

EXAMPLE 11(5α,6α)-6-[(2-Cyanophenyl)methyl]oxy-7,8-didehydro-4,5-epoxy-17-methyl-morphinan-3-olacetate

C₂₇ H₂₈ N₂ O₅

MW: 460.53 gmol⁻¹

¹³ C NMR (100 MHz, CDCl₃) δ 146.2, 141.4, 138.6, 132.9, 132.7, 130.1,129.4, 129.2, 128.3, 125.2, 119.1, 117.3, 117.1, 111.7,89.1, 74.9, 68.9,58.5, 50.1, 46.2, 43.2, 42.4, 40.5, 35.3, 20.4.

EXAMPLE 12(5α,6α)-6-[3-(Methoxycarbonyl)phenylmethyl]oxy-7,8-didehydro-4,5-epoxy-17-methyl-morphinan-3-olacetate

C₂₈ H₃₁ NO₇

MW: 493.56 gmol⁻¹

¹³ C NMR (100 MHz, CDCl₃) δ 172.1, 166.3, 146.3, 139.5, 138.7, 132.6,130.8, 130.3, 129.8, 129.4, 128.8, 128.3, 128.2, 118.6, 116.4, 88.6,73.9, 69.5, 58.2, 52.2, 46.1, 43.0, 42.7, 40.5, 35.5, 21.2, 20.3.

EXAMPLE 13

(5α,6α)-7,8-Didehydro-4,5-epoxy-methoxymethoxy-17-methyl-6-[2-(methoxycarbonyl)phenylmethyl]oxy-morphinane

C₂₈ H₃₁ NO₆

MW: 477.56 gmol⁻¹

¹³ C NMR (100 MHz, CDCl₃) δ 167.4, 148.7, 141.0, 138.8, 132.2, 131.4,130.7, 130.1, 128.8, 128.7, 127.7, 127.6, 126.7, 118.9, 118.4, 96.0,89.6, 74.4, 68.7, 58.8, 56.1, 51.8, 46.4, 43.3, 43.0, 41.0, 35.8, 20.6.

EXAMPLE 14(5α,6α)-7,8-Didehydro-4,5-epoxy-17-methyl-6-[2-(methoxycarbonyl)phenylmethyl]oxy-morphinan-3-olacetate

C₂₈ H₃₁ NO₇

MW: 493.56 gmol⁻¹

¹ H-NMR (CDCl₃) 1.8-2.6 (4H, m, 15-H₂ and 16-H₂), 2.29 (1H, dd, J_(gem)=18.0 and J₁₀.9 =6.0 Hz, 10-H.sub.α), 2.40 (3H, s, N--CH₃), 2.61 (1H, m,14-h), 3.06 (1H, d, J=18.2 Hz, 10-H.sub.β), 3.41 (1H, q, J₉.10 =6.2 Hz,9-H), 4.09 (1H, m), 4.84 (1H, dd, J₅,6, 6=6.0 Hz and J₅,7 =1.1 Hz, 5-H),5.00 (1H, d, J=6.0 Hz), 5.31 (1H, m, 8-H), 5.72 (1H, m, 7-H), 6.38-6.58(2H, AB system, J=8.2 Hz, 1-H and 2-H), 7.50 (2H, d, J=10.2 Hz), 8.002H, d, J=11.4 Hz).

EXAMPLE 15(5α,6α)-7,8-Didehydro-4,5-epoxy-6-[[5-hydroxy-6-(hydroxymethyl)-benzylacetal-2-pyridinyl]methyl]oxy-17-methyl-morphinane

C₃₃ H₃₄ N₂ O₆

MW: 554.65 gmol⁻¹

¹³ C NMR (100 MHz, CDCl₃) δ 150.9, 148.7, 148.4, 140.4, 138.7, 136.1,131.0, 130.3, 129.3, 128.6, 128.5, 128.2, 126.1, 124.3, 121.5, 118.8,118.2, 99.1, 95.8, 89.3, 73.7, 71.1, 68.4, 58.6, 56.0, 46.2, 43.0, 42.7,40.7, 35.5, 20.4.

EXAMPLE 16(5α,6α)-7,8-Didehydro-4,5-epoxy-6-[[5-hydroxy-6-(hydroxymethyl)-2-pyridinyl]methyl]oxy-17-methyl-morphinan-3-olacetate

C₂₆ H₃₀ NO₇. 1/3 C₆ H₁₅ N

MW: 482.54 gmol⁻¹ +33.67 gmol⁻¹ =516.21 gmol⁻¹

ES-MS m/z 423 (M+1)

EXAMPLE 17(5α,6α(-6-[(3-Cyanophenyl)methyl]oxy-7,8-didehydro-4,5-epoxy-3-methoxymethoxy-17-methyl-morphinane

C₂₇ H₂₈ N₂ O₄

MW: 444.53 gmol⁻¹

¹³ C NMR (100 MHz, CDCl₃) δ 148.3, 140.0, 139.0, 131.6, 131.0, 130.2,128.9, 128.4, 119.1, 118.7, 118.0, 112.4, 95.8, 89.2, 73.7, 69.3, 58.9,56.1, 53.3, 46.4, 43.0, 42.9, 10.8, 20.5.

EXAMPLE 18(5α,6α(-6-[(3-Cyanophenyl)methyl]oxy-7,8-didehydro-4,5-epoxy-17-methyl-morphinan-3-olacetate

C₂₇ H₂₃ N₂ O₅

MW: 460.53 gmol⁻¹

¹ H-NMR (DMSO) 1.6-2.3 (4H, m, 15-H₂ and 16-H₂), 2.10 (3H, s, Ac), 2.37(1H, dd, J_(gem) =16.6 and J₁₀,9 =4.4 Hz, 10-H.sub.α), 2.33 (3H, s,N--CH₃), 2.59 (1H, m, 14-H), 2.88 (1H, d, J=17.8 Hz, 10-H.sub.β), 3.30(1H, q, J₉.10 =5.6 Hz, 9-H), 4.07 (1H, m), 4.60-4.78 (2×H, 2× d, J=8.8Hz), 5.00 (1H, d, J₅,6 =6.7 Hz and J₅,7 =1.2 Hz, 5-H), 5.33 (1H, m,8-H), 5.62 (1H, m, 7-H), 6.34-6.47 (2H, AB system, J =12.4 Hz, 1-H and2-H), 7.55 (1H, t, J=7,8 Hz), 7.55 (2H, m) 7,86 (1H, s)

EXAMPLE 19(5α,6α)-6-[4-(2-t-Butyl-5-tetrazolyl)-phenylmethyl]oxy-7,8-didehydro-4,5-epoxy-3-methoxymethoxy-17-methyl-morphinane

C₃₁ H₃₇ N₅ O₄

MW: 543.67 gmol⁻¹

¹³ C NMR (100 MHz, CDCl₃) δ 164.3, 148.6, 140.3, 138.9, 131.2, 130.6,128.8, 128.7, 127.9, 127.2, 126.8, 119.0, 118.3, 96.0, 89.7, 73.4, 70.3,63.7, 58.9, 56.2, 46.2, 43.3, 43.0, 41.0, 35.8, 29.3, 20.6.

EXAMPLE 20(5α,6α)-6-[4-(2-t-Butyl-5-tetrazolyl)-phenylmethyl]oxy-7,8-didehydro-4,5-epoxy-17-methyl-morphinan-3-olacetate

C₃₁ H₃₇ N₅ O₅

MW: 559.67 gmol⁻¹

¹ H-NMR (DMSO) 1.74 (9H, s, 3×CH₃), 1.8-2.6 (5H, m, 10-H.sub.α, 15-H₂and 16-H₂), 1.98 (3H, s, Ac), 2.33 (3H, s, N--CH₃), 2.56 (1H, m, 14-H),3.00 (1H, d, J=18.6 Hz, 10-H.sub.β), 3.31 (1H, q, J₉,10 =6.4 Hz, 9-H),3.99 (1H, m, 6-H), 4.65 (1H, d, J=12 Hz), 4.80 (1H, d, J=12 Hz), 5.01(1H, d, J=6 Hz), 5.32 (1H, m), 5.66 (1H, m), 6.36 (1H, d, J=8.0 Hz),6.42 (1H, d, J=8.0 Hz), 7.59 (2H, d, J =8.0 Hz), 8.04 (2H, d, J=8.0 Hz)

EXAMPLE 21(5α,6α)-7,8-Didehydro-4,5-epoxy-6-[4-(hydroxymethyl)-phenylmethyl]-3-methoxymethoxy-17-methyl-morphinane

C₂₇ H₃₁ NO₆

MW: 449.55 gmol⁻¹

¹³ C NMR (100 MHz, CDCl₃) δ 148.5, 140.7, 138.8, 137.4, 131.2, 130.7,128.6, 127.8, 126.9, 119.0, 118.3, 96.1, 89.6, 73.1, 70.3, 64.7, 58.7,46.3, 43.1, 42.8, 40.7, 35.5, 20.5.

EXAMPLE 22(5α,6α)-7,8-Didehydro-4,5-epoxy-6-[4-(hydroxymethyl)-phenylmethyl]-17-methyl-morphinan-3-olacetate

C₂₇ H₃₁ NO₆

MW: 465.55 gmol⁻¹

¹ H-NMR (DMSO) 1.6-2.3 (4H, m, 15-H₂ and 16-H₂), 1.89 (3H, s, Ac), 2.45(1H, dd, J_(gem=) 16.0 and J₁₀,9 =4.0 Hz, 10-Hα), 2.54 (3H, s, N--CH₃),2.59 (1H, m, 14-H), 2.88 (1H, d, J=18.6 Hz, 10-H.sub.β), 3.26 (1H, q,J₉,10 =5.0 Hz, 9-H), 4.01 (1H, m, 6-H), 4.48 (2H, s), 4,53-4.67 (2×H,2×d, J=9.4 Hz), 5.00 1H, dd, J₅,6 =7.0 Hz and J₅,7 =1.0 Hz, 5-H), 5.33(1H, m, 8-H), 5.63 (1H, m, 7-H), 6.33-6.45 (2H, AB system, J=12.0 Hz,1-H and 2-H), 7.28 (2H, d, J=8.1 Hz), 7.34 (3H, d, J=8.1 Hz).

EXAMPLE 23(5α,6α)-7,8-Didehydro-4,5-epoxy-6-[4-(ethoxycarbonyl)-phenylmethyl]oxy-3-methoxymethoxy-17-methyl-morphinan

C₂₉ H₃₃ NO₆

MW: 491.59 gmol⁻¹

¹³ C NMR (100 MHz, CDCl₃) δ 166.4, 148.5, 143.5, 138.9, 131.2, 130.5,129.7, 129.6, 128.9, 128.7, 128.1, 119.1, 118.3, 96.0, 89.6, 73.7, 70.1,60.8, 58.9, 56.2, 46.4, 43.2, 43.0, 41.0, 35.8, 20.6, 14.3.

EXAMPLE 24(5α,6α)-7,8-Didehydro-4,5-epoxy-6-[4-(ethoxycarbonyl)-phenylmethyl]oxy-17-methyl-morphinan-3-olacetate

C₂₇ H₃₁ NO₆

MW: 507.59 gmol⁻¹

¹ H-NMR (DMSO) 1.31 (3H, t, J=7.3 Hz, CH₃), 1.8-2.6 (4H, m, 15-H₂ and16-H₂), 1.89 (3H, s, AcOH), 2.25 (1H, dd, J_(gem=) 18.0 and J₁₀,9 =5.8Hz, 10-Hα), 2.31 (3H, s, N--CH₃), 2.56 (1H, m, 14-H), 2.87 (1H, d,J=18.5 Hz, 10-H.sub.β), 3.26 (1H, q, J₉,10 =6.4 Hz, 9-H), 4.02 (1H, m,6-H), 4.30 (2H, q, J=7.3 Hz, CH₂), 4.65-4.81 (2×1H, 2×d, 2×J=12.7 Hz),5.00 (1H, m, 5-H), 5.33 (1H, m), 5.65 (1H, m), 6.33-6.45 (2H, AB system,J=8.0 Hz), 7.55 (2H, d, J=8.0 Hz), 7.94 (2H, d, J=8.0 Hz).

Example A

    ______________________________________                                        Haffner test in mice, ED.sub.50 values in nmol/kg, p.o.                                   ED.sub.50 [nmol/kg]                                               Compound    30 min. 60 min.   120 min.                                                                             180 min.                                 ______________________________________                                        5            60      68        72     90                                        Morphine.HCl 279 296 539 718                                                ______________________________________                                    

    ______________________________________                                        Haffner test in mice, ED.sub.50 values in nmol/kg, i.v.                                   ED.sub.50 [nmol/kg]                                               Compound    10 min. 30 min.   60 min.                                                                              120 min.                                 ______________________________________                                        5           0.8     0.8       3.2    9.5                                        Morphine.HCl 17 19 21 37                                                    ______________________________________                                    

4) 7,8-DIHYDROMORPHINE ETHERS CONTAINING A CYCLIC GROUP EXAMPLE 14,5α-Epoxy-17-methyl-6α-((4-(methyloxycarbonyl)-phenyl)-methoxy)-morphinan-3-olacetate

4,5α-Epoxy-3-methoxymethoxy-17-methyl-morphinan-7-en-6α-ol

See Example 1 of "Ethers" above.

4,5α-Epoxy-3-methoxymethoxy-17-methyl-6α-((4-(methyloxycarbonyl)-phenyl)-methoxy)-morphinan-7-ene

NaH (50% suspension in mineral oil, 1.44 mg, 60 mmol) is washed 3× withn-pentane (8 ml) and stirred with absolute dimethylformamide (24 ml) atambient temperature. Then a solution of HN-52084 (3.95 g, 12 mmol) indimethylformamide (24 ml) is added. After the development of gas hasceased, a solution of methyl bromo-4-tolylate (1.38 g, 6 mmol) indimethylformamide (16 ml) is slowly added dropwise. The resultingmixture is then stirred for 2 hours at ambient temperature. The reactionmixture is poured onto water (150 ml) and extracted 3× with methylenechloride (80 ml). The methylene chloride phases are combined, dried overNa₂ SO₄, filtered and concentrated by rotary evaporation. The residuethus obtained is purified by flash chromatography (90 g silica gel;mobile phase: methylene chloride/methanol=9:1). Yield: 2.12 g4,5α-epoxy-3-methoxymethoxy-17-methyl-6α-((4-(methyloxycarbonyl)-phenyl)-methoxy)-morphinan-7-ene(74%).

4,5α-Epoxy-3-methoxymethoxy-17-methyl-6α-((4-(methyloxycarbonyl)-phenyl)-methoxy)-morphinane.

A solution of4,5α-epoxy-3-methoxymethoxy-17-methyl-6α-((4-(methyloxycarbonyl)-phenyl)-methoxy)-morphinan-7-ene(1.90 g, 3.98 mmol) in MeOH (70 ml) is mixed with 10% Pd/C (1.17 g) andagitated for 0.5 hours under 1 bar of H₂ pressure. The catalyst isremoved by filtering through Celite and the filtrate is evaporated down.The residue is purified by flash chromatography (silica gel; mobilephase: dichloromethane: MeOH=3:1). Yield: 1.44 g4,5α-epoxy-3-methoxymethoxy-17-methyl-6α-((4-(methyloxycarbonyl)-phenyl)-methoxy)-morphinane(75.4%).

¹³ C NMR (100 MHz, CDCl₃) δ 167.0, 147.7, 144.5, 139.0, 130.4, 129.3,128.7, 127.8, 126.3, 118.5, 117.2, 95.6, 89.9, 74.7, 71.1, 59.8, 56.0,51.9, 47.2, 42.9, 42.2, 41.8, 37.0, 26.0, 20.3, 19.0.

4,5α-Epoxy-17-methyl-6α-((4-(methyloxycarbonyl)-phenyl)-methoxy)-morphinan-3-olacetate.

4,5α-Epoxy-3-methoxymethoxy-17-methyl-6α-((4-(methyloxycarbonyl)-phenyl)-methoxy)-morphinane(1.40 g, 2.92 mmol) is dissolved with water (35 ml) and glacial aceticacid (35 ml) and then stirred for 4 hours at 100° C. The volatilecomponents are eliminated using the Rotavapor. The residue thus obtainedis purified by flash chromatography (100 g of silica gel; mobile phase:methylene chloride/methanol= 4:1). The product is dissolved in a mixtureof water and glacial acetic acid and lyophilised. Yield: 1.225 g4,5α-epoxy-17-methyl-6α-((4-(methyloxycarbonyl)-phenyl)-methoxy)-morphinan-3-olacetate (84.7%).

¹³ C NMR (100 MHz, CDCl₃) δ 176.7, 167.0, 145.8, 144.1, 139.4, 129.3,128.8, 128.3, 126.4, 121.0, 118.8, 117.7, 88.9, 74.3, 60.5, 52.0, 47.3,40.7, 38.5, 34.2, 25.6, 22.1, 21.2, 18.1.

The following compounds were prepared analagously to Example 1.

EXAMPLE 24,5α-Epoxy-6α-[(4'-methoxycarbonyl)phenylmethyl]oxy-17-methyl-morphine

C₂₈ H₃₃ NO₇

MW: 495.58 gmol⁻¹

¹³ CNMR(100 MHz CDCl₃) δ 167.0, 147.7, 144.5, 139.0, 130.4, 129.3,128.7, 127.8, 126.3, 118.5, 117.2, 95.6, 89.9, 74.7, 71.1, 59.8, 56.0,51.9, 47.2, 41.8, 37.0, 26.0, 20.3, 19.0.

EXAMPLE 34,5α-Epoxy-6α-[(4'-methoxycarbonyl)phenylmethylloxy-17-methyl-morphin-3-olacetate

C₂₈ H₃₃ NO₇

MW: 495.58 gmol⁻¹

¹³ CNMR(100 MHz CDCl₃) δ 176.7, 167.0, 145.8, 144.1, 139.4, 129.3,128.8, 128.3, 126.4, 121.0, 118.8, 117.7,88.9, 74.3, 71.5, 60.5, 52.0,47.3, 40.7, 38.5, 34.2, 25.6, 22.1, 21.2, 18.1.

Example A

    ______________________________________                                        Haffner test in mice, ED.sub.50 values in nmol/kg, p.o.                                  ED.sub.50 [nmol/kg]                                                Compound   30 min.  60 min.  120 min.                                                                              180 min.                                 ______________________________________                                        1           55       73       87     103                                        7,8-Dihydro- 177 195 250 481                                                  morphine.AcOH                                                                 Morphine.HCl 279 296 539 718                                                ______________________________________                                    

    ______________________________________                                        Haffner test in mice, ED.sub.50 values in nmol/kg, i.v.                                  ED.sub.50 [nmol/kg]                                                Compound   10 min.  30 min.  60 min. 120 min.                                 ______________________________________                                        1           2       3.2      12      52                                         7,8-Dihydro- 16 23 32 130                                                     morphine.AcOH                                                                 Morphine.HCl 17 19 21 37                                                    ______________________________________                                    

5) ESTERS EXAMPLE 1 4,5α-Epoxy-6α-((4-methoxycarbonyl-butyryl)-oxy)-3-methoxymethoxy-17-methyl-morphinan-7-ene

4,5α-Epoxy-3-methoxymethoxy-17-methyl-morphinan-7-en-6α-ol

See Example 1 of "Ethers" above

4,5α-epoxy-6α-((4-methoxycarbonyl-butyryl)-oxy)-3-methoxymethoxy-17-methyl-morphinan-7-ene

4,5α-Epoxy-3-methoxymethoxy-17-methyl-morphinan-7-en-6α-ol (2.0 g, 6.1mmol) and 4-dimethylaminopyridine (0.8 g, 6.5 mmol) were dissolved inabsolute CH₂ Cl₂ (20 ml) and methyl glutarate chloride (1.0 g, 6.08mmol) were added dropwise whilst cooling with ice and the mixture wasstirred for 2 hours at this temperature. The reaction mixture was pouredonto water (50 ml), the organic phase was washed twice more with 30 mlof water and dried over MgSO₄. The solvent was evaporated off and theresidue was separated off by flash chromatography (CH₂ Cl₂ /MeOH 9/1).

Yield: 2.2 g (78.5%)4,5α-epoxy-6α-((4-methoxycarbonyl-butyryl)-oxy)-3-methoxymethoxy-17-methyl-morphinan-7-eneas a colourless oil

¹³ C NMR (CDCl₃) δ 173.3, 172.3, 147.9, 139.0, 131.0, 129.6, 128.7,128.4, 119.3, 118.3, 96.0, 88.1, 68.3, 59.0, 56.2, 51.5, 46.6, 43.0,42.8, 40.7, 35.4, 33.1, 33.1, 20.5, 20.1; ES MS m/z 458.5 (M+H)⁺ ; C₂₅H₃₁ NO₇ (MW=457.54).

EXAMPLE 24,5-Epoxy-6α-(4-methoxycarbonyl-butyryl)-oxy)-17-methyl-morphinan-7-en-3-olacetate

A solution of4,5α-epoxy-6α-((4-methoxycarbonyl-butyryl)-oxy)-3-methoxymethoxy-17-methyl-morphinan-7-ene(2.0 g, 4.4 mmol) in glacial acetic acid (60 ml) is mixed with water (60ml) and refluxed for 6 hours under N₂. After cooling, the solvent isevaporated off and the residue is separated by flash chromatography(silica gel; mobile phase: CH₂ Cl₂ :MeOH=9:1). After the elimination ofthe solvent, the residue was dissolved in 2 ml of glacial acetic acidand 15 ml of water and freeze-dried overnight.

Yield: 0.64 g of lyophilised4,5α-epoxy-6α-((4-methoxycarbonyl-butyryl)-oxy)-17-methyl-morphinan-7-en3-ol acetate

¹³ C NMR (CDCl₃) δ 176.2, 174.2, 172.2, 145.5, 138.8, 129.8, 128.9,128.6, 124.7, 119.7, 117.3, 87.8, 68.2, 59.1, 51.9, 46.6, 42.6, 42.2,39.5, 34.5, 33.1, 33.0, 22.3, 20.9, 20.5; ES MS m/z 414.5 (M+H)⁺ ; C₂₃H₂₇ NO₆ (MW=413.48+60.02).

The following were prepared analogously:

EXAMPLE 34,5α-Epoxy-3-methoxymethoxy-6α-((3-methoxy-propionyl)-oxy)-17-methyl-morphinan-7-ene

¹³ C NMR (100 MHz, CDCl₃) δ 171.1, 148.0, 139.1, 131.2, 129.8, 129.4,128.9, 128.5, 119.5, 118.5, 96.1, 68.6, 68.0, 59.2, 58.9, 56.4, 46.8,43.2, 42.9, 41.4, 40.8, 36.0, 35.5, 34.9, 20.7; ES MS m/z 416.4 (M+H)⁺ ;C₂₃ H₂₉ NO₆ (MW 415.49)

EXAMPLE 44,5α-Epoxy-6α-((methoxy-acetyl)-oxy)-3-methoxymethoxy-17-methyl-morphinan-7-ene

¹³ C NMR (100 MHz, CDCl₃) δ 169.9, 148.1, 139.1, 131.0, 129.9, 128.8,128.0, 119.5, 118.6, 118.4, 96.2, 88.0, 69.6, 68.5, 59.2, 56.2, 46.7,43.0, 42.7, 40.7, 35.4, 20.6; C₂₂ H₂₇ NO₆ (MW 401.46).

EXAMPLE 54,5α-Epoxy-3-methoxymethoxy-6α-((3-methylthio-propionyl)-oxy)-17-methyl-morphinan-7-ene

¹³ C NMR (100 MHz, CDCl₃) δ 171.3, 147.8, 138.9, 130.9, 129.6, 128.6,128.2, 119.3, 118.2, 95.9, 88.0, 68.3, 59.0, 56.1, 46.53, 42.9, 42.6,40.6, 35.3, 34.3, 28.9, 20.4, 15.3; ES MS m/z 432.5 (M+H⁺); C₂₃ H₂₉ NO₅S (MW 431.55).

EXAMPLE 64,5α-Epoxy-6α-((3-methoxy-propionyl)-oxy)-17-methyl-morphinan-7-en-3-olacetate

¹³ C NMR (100 MHz, CDCl₃) δ 176.1, 170.9, 144.5, 139.2, 129.2, 128.8,127.8, 123.3, 120.0, 117.4, 86.0, 68.5, 67.0, 59.4,58.9, 46.9, 41.6,40.9, 38.4, 34.6, 33.4, 22.1; 20.9; ES MS m/z 372.8 (M⁺ -59) C₂₃ H₂₉ NO₇(MW 431.4).

EXAMPLE 74,5α-Epoxy-6α-((methoxy-acetyl)-oxy)-17-methyl-morphinan-7-en-3-olacetate

¹³ C NMR (100 MHz, CDCl₃) δ 176.7, 169.9, 145.6, 139.5, 129.4, 129.1,128.2, 123.6, 120.3, 118.1, 87.2, 70.0, 67.9, 59.8, 59.6, 47.0, 41.8,41.6, 38.4, 33.5, 22.0, 21.6; ES MS m/z 358.5 (M⁺ -59) C₂₂ H₂₇ NO₇ (MW417.46).

EXAMPLE 84,5α-Epoxy-6α-((3-methylthio-propionyl)-oxy)-17-methyl-morphinan-7-en-3-olacetate

¹³ C NMR (100 MHz, CDCl₃) δ 176.5, 171.3, 145.1, 139.1, 129.3, 128.9,128.0, 123.6, 119.8, 117.3, 87.1, 67.7, 59.1, 46.6, 41.7, 41.5, 38.5,34.4, 33.5, 29.2, 22.2, 21.1, 15.8; C₂₃ H₂₉ NO₆ (MW 387.50).

EXAMPLE 94,5α-Epoxy-6α-((3,3-dimethyl-butyryl)-oxy)-17-methyl-morphinan-7-en-3-olacetate

¹³ C NMR (100 MHz, CDCl₃) δ 176.3, 171.7, 145.6, 138.6, 129.6, 129.2,128.3, 124.4, 119.7, 117.1, 88.3, 68.0, 58.9, 47.7, 46.3, 42.6, 41.7,39.0, 34.0, 30.8, 29.6, 22.1, 21.1.

EXAMPLE 104,5α-Epoxy-6α-((3,3-dimethyl-butyryl)-oxy)-3-methoxy-methoxy-morphinan-7-ene

¹³ C NMR (100 MHz, CDCl₃) δ 171.3, 147.8, 138.5, 130.7, 129.2, 128.4,128.2, 118.8, 118.2, 95.7,88.2, 68.0, 58.6, 55.8, 47.4, 46.1, 42.7,42.6, 40.4, 35.1, 30.3, 29.3, 20.2.

EXAMPLE 114,5α-Epoxy-17-methyl-6α-((2-trifluoromethyl-2-hydroxy-propionyl)-oxy)-morphinan-7-en-3-olacetate ES MS m/z 426.5 (M+H⁺) EXAMPLE 124,5α-Epoxy-17-methyl-6α-((3-methoxycarbonyl-propionyl)-oxy)-morphinan-7-en-3-olacetate

¹³ C NMR (100 MHz, DMSO-d₆) δ 172.5, 172.1, 171.5, 145.3, 138.9, 130.4,130.0, 128.1, 125.0, 119.0, 116.6, 87.1, 68.1, 58.3, 51.5, 46.3, 42.6,42.1, 34.7, 28.7, 21.2, 20.1.

EXAMPLE 134,5α-Epoxy-17-methyl-6α-((3-ethyloxycarbonyl-acryloyl)-oxy)-morphinan-7-en-3-olacetate

¹³ C NMR (100 MHz, DMSO-d₆) δ 172.1, 154.4, 163.9, 145.3, 138.9, 133.6,133.1, 130.4, 130.3, 127.6 125.1, 119.1, 116.6, 86.9, 69.1, 61.2, 58.3,46.3, 42.7, 42.2, 39.1, 34.8, 21.2, 20.1, 14.0.

EXAMPLE 144,5α-Epoxy-17-methyl-6α-((2-methylthio-acetyl)-oxy)-morphinan-7-en-3-olacetate

¹³ C NMR (100 MHz, CDCl₃) δ 176.7, 169.5, 145.5, 139.6, 129.4, 129.2,127.9, 123.3, 120.4, 118.0, 87.3, 68.2, 59.6, 47.0, 41.7, 41.6, 38.2,35.4, 33.3, 22.2, 21.6, 16.5.

EXAMPLE 154,5α-Epoxy-3-methoxymethoxy-17-methyl-6α-((2-trifluoromethyl-2-hydroxy-propionyl)-oxy)-morphinan-7-eneES MS m/z 470.3 (M+H⁺) EXAMPLE 164,5α-Epoxy-6α-((3-methoxycarbonyl-propionyl)-oxy)-3-methoxymethoxy-17-methyl-morphinan-7-ene

¹³ C NMR (100 MHz, CDCl₃) δ 172.6, 171.7, 147.8, 139.0, 131.0, 129.6,128.7, 128.2, 119.3, 118.3, 96.0, 88.1, 68.5, 59.0, 56.2, 51.7, 46.6,43.0, 42.7, 40.7, 35.3, 29.0, 20.5.

EXAMPLE 174,5α-Epoxy-6α-((3-ethyloxycarbonyl-acryloyl)-oxy)-3-methoxymethoxy-17-methyl-morphinan-7-ene

¹³ C NMR (100 MHz, CDCl₃) δ 164.8, 164.3, 147.7, 139.1, 134.3, 133.1,130.9, 130.0, 128.6, 127.8, 119.5, 118.2, 95.9, 87.9, 69.1, 61.3, 59.1,56.2, 46.6, 43.0, 42.8, 40.7, 35.3, 20.5, 14.1.

EXAMPLE 184,5α-Epoxy-3-methoxymethoxy-17-methyl-6α-((2-methylthio-acetyl)-oxy)-morphinan-7-ene

¹³ C NMR (100 MHz, CDCl₃) δ 170.1, 148.2, 139.3, 131.3, 130.2, 129.0,128.3, 119.7, 118.7, 96.3, 88.4, 69.5, 59.3, 56.5, 46.9, 43.3, 43.2,41.0, 35.8, 35.7, 20.8, 16.6.

EXAMPLE 194,5α-Epoxy-6α-((5-methoxycarbonyl-valeryl)-oxy)-3-methoxymethoxy-17-methyl-morphinan-7-ene

¹³ C NMR (100 MHz, CDCl₃) δ 173.7, 172.6, 147.8, 138.9, 130.97, 129.5,128.6, 128.4, 119.2, 118.3, 95.9, 88.1, 68.2, 59.0, 56.1, 51.4, 46.5,42.9, 42.7, 40.6, 35.3, 33.6, 24.3, 24.2, 20.5.

EXAMPLE 204,5α-Epoxy-6α-((5-methoxycarbonyl-valeryl)-oxy)-17-methyl-morphinan-7-en-3-olacetate

¹³ C NMR (100 MHz, CDCl₃) δ 176.6, 174.2, 172.6, 145.6, 139.2, 129.1,127.6, 123.0, 119.5, 117.5, 87.3, 67.6, 59.0, 51.6, 46.4, 41.9, 41.3,38.3, 33.5, 33.4, 24.2, 24.1, 22.3, 21.2.

EXAMPLE 214,5α-Epoxy-6α-((6-methoxycarbonyl-hexylcarbonyl)-oxy)-3-methoxymethoxy-17-methyl-morphinan-7-en-3-ol

¹³ C NMR (100 MHz, CDCl₃) δ 174.3, 173.3, 148.3, 139.2, 131.4, 129.9,129.1, 128.8, 119.6, 118.7, 96.3, 88.6, 68.5, 59.3, 56.5, 53.7, 51.7,469.9, 43.3, 43.2, 41.1, 35.7, 34.3, 29.0, 25.0, 24.9, 20.8.

EXAMPLE 224,5α-Epoxy-6α-((6-methoxycarbonyl-hexylcarbonyl)-oxy)-17-methyl-morphinan-7-en-3-ol

¹³ C NMR (100 MHz, CDCl₃) δ 176.0, 174.2, 172.7, 145.2, 138.6, 129.2,128.8, 127.7, 123.6, 119.3, 116.9, 87.4, 67.3, 58.7, 51.2, 46.1, 41.8,41.3, 38.4, 33.6, 33.4, 28.3, 24.2, 21.7, 20.8.

EXAMPLE 23 Morphine-6-O-methyl -2,3-O-diacetyl-L_(g) -tartate

C₂₈ H₃₅ NO₁₁

Salt form: Acetate

MW: 561.59 gmol⁻¹

¹³ C NMR (100 MHz, CDCl₃) δ 175.8, 170.6, 169.6, 166.1, 165.1, 144.1,139.0, 128.9, 128.7, 127.8, 123.5, 120.3, 117.4, 85.8, 71.4, 70.1, 68.5,59.3, 53.1, 46.9, 41.6, 41.0, 38.3, 33.4, 21.6, 20.8, 20.5, 20.3.

Example A

                  TABLE 1                                                         ______________________________________                                        Haffner test in mice, % MPE, ED.sub.50 values i.v.                              Compound                                                                      according to ED.sub.50 [nmol/kg]                                            Example     10 min. 30 min.   60 min.                                                                             120 min.                                  ______________________________________                                        11          5.6     7         13    19                                          20 3.7 5.1 11 15                                                              22 2.5 3.3  5 22                                                               2 3.4 4.2  9 12                                                              Morphine.HCl 17 19 21 37                                                    ______________________________________                                    

                  TABLE 2                                                         ______________________________________                                        Haffner test in mice, ED.sub.50 values in nmol/kg, p.o.                           Compound                                                                    according to ED.sub.50 [nmol/kg]                                            Example     30 min. 60 min.   120 min.                                                                             180 min.                                 ______________________________________                                        11          148     172       256    269                                        20 118 120 170 234                                                            22 109 208 298 315                                                             2 126 128 148 175                                                            Morphine.HCl 279 296 539 718                                                ______________________________________                                    

6) ESTERS CONTAINING A CYCLIC GROUP EXAMPLE 14,5α-Epoxy-17-methyl-6α-((2-thienyl)-acetyloxy)-morphinan-7-en-3-olacetate

4,5α-Epoxy-3-methoxymethoxy-17-methyl-morphinan-7-en-6α-ol

See Example 1 of "Ethers" above

4,5α-Epoxy-3-methoxymethoxy-17-methyl-6α-((2-thienyl)-acetyloxy)-morphinan-7-ene

4,5α-Epoxy-3-methoxymethoxy-17-methyl-morphinan-7-en-6α-ol (1.98 g, 6mmol) and thiophene-2-acetic acid (0.853 g, 6 mmol) are dissolved in CH₂Cl₂ (30 ml) at 25° C. Then N,N'-dicyclohexylcarbodiimide (1.24 g, 6mmol) and 4-dimethylaminopyridine (0.73 g, 6 mmol) are added to thestirred solution. After the solution has been stirred for a further 14hours at 25° C., the precipitate is filtered off and washed with CH₂ Cl₂(20 ml). The combined organic phase is washed with water (2×10 ml),dried (Na₂ SO₄), filtered and evaporated down using a Rotavapor. Theresidue thus formed is purified by flash chromatography (silica gel;mobile phase: CH₂ Cl₂ :MeOH=9:1). The residue is freed from residualsolvent in a high vacuum in order to obtain4,5α-epoxy-3-methoxymethoxy-17-methyl-6α-((2-thienyl)-acetyloxy)-morphinan-7-ene(2.07 g, 76.1%) as a colourless foam.

¹³ C NMR (100 MHz, CDCL₃) δ 169.6, 147.5, 138.6, 134.5, 130.6, 129.4,128.4, 127.7, 126.5, 126.4, 124.6, 119.0, 118.1, 95.66, 87.7, 68.6,58.6, 55.9, 46.2, 42.7, 42.4, 40.3, 35.0, 34.7, 20.2.

4,5α-Epoxy-17-methyl-6α-((2-thienyl)-acetyloxy)-morphinan-7-en-3-olacetate

A solution of4,5α-epoxy-3-methoxymethoxy-17-methyl-6α-((2-thienyl)-acetyloxy)-morphinan-7-ene(1.00 g, 2.20 mmol) in glacial acetic acid (30 ml) is mixed with (30 ml)of water and stirred for 5 hours at 100° C. under N₂. The solution isevaporated down using a Rotavapor. The residue obtained is purified byflash chromatography (silica gel; mobile phase: CH₂ Cl₂ :MeOH=9:1) andlyophilised in order to obtain4,5α-epoxy-17-methyl-6α-((2-thienyl)-acetyloxy)-morphinan-7-en-3-olacetate (0.444 g, 89.9%) as a colourless foam.

¹³ C NMR (100 MHz, CDCl₃) δ 176.9, 170.2, 145.6, 139.6, 135.2, 129.5,129.2, 127.6, 127.3, 127.2, 125.4, 122.9, 120.3, 117.9, 87.3, 68.3,59.7, 46.9, 41.8, 41.3, 38.0, 35.3, 33.1, 22.0, 21.8.

The following were prepared analogously to Example 1:

EXAMPLE 24,5α-Epoxy-3-methoxymethoxy-17-methyl-6α-(phenyl-acetyloxy)-morphinan-7-ene

¹³ C NMR (100 MHz, CDCl₃) δ 170.7, 147.7, 138.7, 133.6, 130.7, 129.4,129.0, 128.4, 128.2, 128.0, 126.7, 119.0, 118.1, 95.7,87.9, 58.7, 55.9,46.3, 42.7, 42.5, 40.6, 40.4, 35.1, 20.2; ES MS m/z 448.5 (M+H⁺) C₂₇ H₂₉NO₅ (MW 447.54).

EXAMPLE 3 4,5α-Epoxy-17-methyl-6α-(phenyl-acetyloxy)-morphinan-7-en-3-olacetate

¹³ C NMR (100 MHz, CDCl₃) δ 176.44, 170.9, 145.3, 139.1, 133.9, 129.3,129.1, 129.08, 128.6, 128.3, 127.5, 127.2, 123.2, 119.8, 117.4, 87.3,67.9, 59.2, 46.5, 41.7, 41.2, 41.0, 38.1, 33.2, 21.9, 21.3; ES MS m/z404.5 (M⁺ -59) C₂₇ H₂₉ NO₆ (MW 463.54).

EXAMPLE 44,5α-Epoxy-3-methoxymethoxy-17-methyl-6α-((4-chlorophenyl)-acetyloxy)-morphinan-7-ene

¹³ C NMR (100 MHz, CDCl₃) δ 170.2, 147.5, 138.7, 132.7, 132.0, 130.6,130.4, 129.5, 128.4, 128.3, 127.7, 119.0, 118.0, 95.6, 87.7, 68.5, 58.7,55.9, 46.2, 42.7, 42.4, 40.4, 39.9, 35.0, 20.2; ES MS m/z 482.9 (M+H⁺)C₂₇ H₂₈ ClNO₅ (MW 481.98).

EXAMPLE 56α-((4-Chlorophenyl)-acetyloxy)-4,5α-epoxy-17-methyl-morphinan-7-en-3-olacetate

¹³ C NMR (100 MHz, CDCl₃) δ 176.6, 170.5, 145.3, 139.2, 133.1, 132.3,130.8, 129.1, 129.0, 128.7, 127.7, 123.1, 119.8, 117.5, 87.1, 68.0,59.2, 46.5, 41.7, 41.3, 40.1, 38.1, 33.2, 22.1, 21.3; ES MS m/z 482.9(M⁺ -59) C₂₇ H₂₈ ClNO₆ (MW 481.98).

EXAMPLE 64,5α-Epoxy-3-methoxymethoxy-17-methyl-6α-((3-pyridyl)-acetyloxy)-morphinan-7-ene

¹³ C NMR (100 MHz, CDCl₃) δ 169.8, 150.1, 148.1, 147.3, 138.6, 136.6,130.5, 129.5, 129.3, 128.3, 123.0, 119.1, 117.9, 95.6, 87.5, 68.5, 58.7,55.8, 46.2, 42.6, 37.6, 35.0, 20.1.

EXAMPLE 74,5α-Epoxy-17-methyl-6α-((3-pyridyl)-acetyloxy)-morphinan-7-en-3-olacetate

¹³ C NMR (100 MHz, CDCl₃) δ 175.9, 169.3, 149.7, 146.8, 145.1, 139.2,137.7, 129.8, 128.6, 127.3, 123.4, 122.1, 119.5, 117.9, 86.4, 67.8,58.9, 46.3, 41.2, 40.8, 38.1, 37.6, 32.7, 21.3, 21.0.

EXAMPLE 84,5α-Epoxy-3-methoxymethoxy-17-methyl-6α-((3-thienyl)-acetyloxy)-morphinan-7-ene

¹³ C NMR (100 MHz, CDCl₃) δ 170.5, 147.9, 139.0, 133.4, 131.0, 129.7,128.6, 128.2, 125.5, 123.0, 119.3, 118.3, 96.0, 88.2, 68.8, 59.0, 56.2,46.6, 43.0, 42.8, 40.7, 35.6, 35.4, 20.5.

EXAMPLE 94,5α-Epoxy-17-methyl-6α-((3-thienyl)-acetyloxy)-morphinan-7-en-3-olacetate

¹³ C NMR (100 MHz, CDCl₃) δ 176.6, 170.5, 145.3, 139.1, 133.4, 129.3,128.9, 128.6, 127.9, 125.7, 123.5, 123.1, 119.8, 117.3, 87.4, 68.1,59.1, 46.5, 41.9, 41.4, 38.4, 35.5, 33.5, 22.1, 21.2.

EXAMPLE 106α-((2-Chlorophenyl)-acetyloxy)-4,5α-epoxy-3-methoxymethoxy-17-methyl-morphinan-7-ene

¹³ C NMR (100 MHz, CDCl₃) δ 169.7, 147.6, 138.6, 134.3, 132.0, 131.2,130.7, 129.4, 129.1, 128.4, 128.3, 127.9, 126.5, 119.0, 118.1,95.7,87.9, 68.6, 58.7, 55.9, 46.2, 42.7, 42.5, 40.4, 38.3, 35.1, 20.2.

EXAMPLE 116α-((2-Chlorophenyl)-acetyloxy)-4,5α-epoxy-17-methyl-morphinan-7-en-3-olacetate

¹³ C NMR (100 MHz, CDCl₃) δ 176.6, 170.0, 145.4, 139.4, 134.5, 132.2,131.7, 129.4, 129.3, 128.9, 128.7, 127.2, 126.9, 122.7, 119.8, 117.5,87.2, 67.9, 59.3, 46.6, 41.6, 41.3., 38.6, 37.8, 33.0, 21.9, 21.4.

EXAMPLE 126α-((3-Chlorophenyl)-acetyloxy)-4,5α-epoxy-3-methoxymethoxy-17-methyl-morphinan-7-ene

¹³ C NMR (100 MHz, CDCl₃) δ 170.4, 147.8, 139.0, 135.7, 134.2, 130.9,129.8, 129.7, 129.5, 128.7, 127.6, 127.3, 119.3, 118.3, 95.9, 87.9,68.8, 59.0, 56.2, 46.6, 43.0, 42.7, 40.7, 40.4, 35.3, 20.5.

EXAMPLE 136α-((3-Chlorophenyl)-acetyloxy)-4,5α-epoxy-17-methyl-morphinan-7-en-3-olacetate

¹³ C NMR (100 MHz, CDCl₃) δ 176.4, 170.0, 145.0, 138.9, 135.4, 133.9,129.4, 129.2, 128.8, 128.6, 127.5, 127.3, 127.0, 122.9, 119.5, 117.2,86.8, 67.7, 58.8, 46.2, 41.4, 41.0, 40.0, 37.9, 33.0, 21.9, 20.9.

EXAMPLE 144,5α-Epoxy-3-methoxymethoxy-6α-(3-(2-methoxyphenyl)-propionyloxy)17-methyl-morphinan-7-ene

¹³ C NMR (100 MHz, CDCl₃) δ 173.0, 157.7, 148.2, 139.1, 131.3, 130.4,130.2, 129.7, 129.0, 128.9, 128.7, 127.8, 120.6, 119.5, 118.6, 110.4,96.2, 88.6, 68.5, 59.2, 56.4,55.3, 46.8, 43.2, 40.9, 35.6, 34.2, 26.2,20.7.

EXAMPLE 154,5α-Epoxy-6α-(3-(2-methoxyphenyl)-propionyloxy)-17-methyl-morphinan-7-en-3-olacetate

¹³ C NMR (100 MHz, CDCl₃) δ 176.4, 172.7, 157.5, 145.3, 139.1, 130.0,129.5, 129.1, 128.8, 127.6, 127.3, 123.1, 120.5, 119.8, 117.4, 110.4,87.5, 67.4, 59.2, 55.3, 46.5, 41.8, 41.2, 38.0, 33.9, 33.1, 25.9, 21.8,21.4.

EXAMPLE 164,5α-Epoxy-3-methoxymethoxy-6α-(3-(4-methoxyphenyl)-propionyloxy)-17-methyl-morphinan-7-ene

¹³ C NMR (100 MHz, CDCl₃) δ 171.9, 157.6, 147.4, 138.5, 132.2, 130.6,129.2, 128.8, 128.3, 128.0, 118.9, 117.8m 113.5, 95.5, 87.8, 67.8, 58.6,55.8, 54.8, 46.2, 42.6, 42.3, 40.3, 35.5, 35.0, 29.6, 20.0.

EXAMPLE 174,5α-Epoxy-6α-(3-(4-methoxyphenyl)-propionyloxy)-17-methyl-morphinan-7-en-3-olacetate

¹³ C NMR (100 MHz, CDCl₃) δ 176.8, 172.7, 158.4, 145.7, 139.4, 132.9,129.6, 129.5, 127.8, 123.5, 120.1, 117.7, 114.3, 87.8, 67.8, 59.5, 55.6,46.8, 42.1, 41.6, 38.5, 36.1, 33.5, 30.3, 22.2, 21.6.

EXAMPLE 184,5α-Epoxy-3-methoxymethoxy-6α-(4-(4-methoxyphenyl)-butyryloxy)-17-methyl-morphinan-7-ene

¹³ C NMR (100 MHz, CDCl₃) δ 173.1, 158.1, 148.2, 139.2, 133.7, 131.2,129.6, 128.9, 128.7, 119.6, 118.6, 114.0, 96.1, 88.5, 68.5, 59.2, 56.3,55.4, 50.7, 46.8, 43.2, 43.0, 40.9, 35.6, 34.4, 33.6, 26.9, 20.7.

EXAMPLE 194,5α-Epoxy-6α-(4-(4-methoxyphenyl)-butyryloxy)-17-methyl-morphinan-7-en-3-olacetate

¹³ C NMR (100 MHz, CDCl₃) δ 176.0, 172.6, 157.6, 145.1, 138.4, 133.1,129.1, 128.7, 127.8, 123.8, 119.4, 116.9, 113.6, 87.6, 67.5, 58.7, 54.9,46.1, 41.3, 38.4, 33.8, 33.0, 26.3, 21.7, 20.8.

EXAMPLE 206α-(Cyclohexylacetyloxy)-4,5α-epoxy-3-methoxymethoxy-17-methyl-morphinan-7-ene

¹³ C NMR (100 MHz, CDCl₃) δ 172.1, 147.7, 138.5, 130.7, 129.2, 128.4,128.2, 118.8, 118.1, 95.6, 93.2, 88.1, 67.9, 58.6, 55.8, 46.2, 42.7,41.5, 40.4, 35.1, 34.4, 32.7, 25.7, 20.2.

EXAMPLE 216α-(Cyclohexylacetyloxy)-4,5α-epoxy-17-methyl-morphinan-7-en-3-olacetate

¹³ C NMR (100 MHz, CDCl₃) δ 176.5, 172.5, 145.5, 139.1, 129.5, 129.1,127.4, 123.2, 119.7, 117.4, 87.8, 67.6, 59.1, 46.5, 42.0, 41.8, 41.2,38.2, 34.7, 33.3, 33.0, 26.1, 26.0, 21.9, 21.4.

EXAMPLE 224,5α-Epoxy-3-methoxymethoxy-6α-((2-methoxyphenyl)-acetyloxy)-17-methyl-morphinan-7-ene

¹³ C NMR (100 MHz, CDCl₃) δ 171.5, 157.8, 148.4, 139.1, 131.4, 131.1,129.7, 129.1, 128.7, 123.2, 120.7, 119.5, 118.9, 110.8, 96.3, 88.7,68.9, 59.2, 56.5, 55.6, 46.8, 43.2, 41.0, 35.6, 20.8.

EXAMPLE 234,5α-Epoxy-6α-((2-methoxyphenyl)-acetyloxy)-17-methyl-morphinan-17-en-3-olacetate

¹³ C NMR (100 MHz, CDCl₃) δ 176.7, 171.0, 157.5, 145.4, 139.3, 131.0,129.3, 129.1, 128.6, 127.4, 122.9, 122.8, 12 0.6, 119.7, 117.4, 110.8,87.2, 67.5, 59.2, 55.7, 46.5, 41.6, 41.2, 38.1, 35.3, 33.1, 22.3, 21.2.

EXAMPLE 244,5α-Epoxy-3-methoxymethoxy-6α-((3-methoxyphenyl)-acetyloxy)-17-methyl-morphinan-7-ene

¹³ C NMR (100 MHz, CDCl₃) δ 170.7, 159.6, 147.8, 138.8, 135.2, 130.9,129.6, 129.3, 128.6, 128.1, 121.6, 119.2, 118.3, 114.9, 112.6, 95.9,88.1, 68 .6, 5 8.9, 5 6.1, 55.0, 46.4, 42.9, 42.7, 40.8, 40.6, 35.3,20.4.

EXAMPLE 254,5α-Epoxy-6α-((3-methoxyphenyl)-acetyloxy)-17-methyl-morphinan-7-en-3-olacetate

¹³ C NMR (100 MHz, CDCl₃) δ 176.5, 170.7, 159.5, 145.4, 139.0, 135.3,129.5, 129.2, 128.9, 128.0, 123.6, 121.7, 119.7, 115.5, 112.1, 87.5,68.2, 59.0, 55.2, 46.4, 42.1, 41.5, 41.0, 38.5, 33.5, 22.2, 21.2.

EXAMPLE 264,5α-Epoxy-3-methoxymethoxy-6α-((4-methoxyphenyl)-acetyloxy)-17-methyl-morphinan-7-ene

¹³ C NMR (100 MHz, CDCl₃) δ 171.2, 158.6, 147.8, 138.8, 130.3, 129.5,128.7, 128.2, 125.9, 119.2, 118.3, 113.9, 95.9, 88.1, 68.6, 58.9, 56.1,55.1, 46.4, 42.9, 42.7, 40.6, 39.9, 35.4, 20.4.

EXAMPLE 274,5α-Epoxy-6α-((4-methoxyphenyl)-acetyloxy)-17-methyl-morphinan-7-en-3-olacetate

¹³ C NMR (100 MHz, CDCl₃) δ 177.0 171.5, 159.0, 145.7, 139.5, 130.7,129.5, 129.4, 128.1, 126.2, 123.7, 120.0, 117.7, 114.3, 87.6, 68.2,59.4, 55.5, 46.8, 42.2, 41.7, 40.3, 38.7, 33.7, 22.6, 21.5.

EXAMPLE 284,5α-Epoxy-17-methyl-6α-((2-nitrophenyl)-acetyloxy)-morphinan-7-en-3-olacetate EXAMPLE 294,5α-Epoxy-17-methyl-6α-((3-nitrophenyl)-acetyloxy)-morphinan-7-en-3-olacetate EXAMPLE 304,5α-Epoxy-17-methyl-6α-((4-nitrophenyl)-acetyloxy)-morphinan-7-en-3-olacetate EXAMPLE 316α-((3-Cyanobenzoyl)oxy)-4,5α-epoxy-17-methyl-morphinan-7-en-3-olacetate EXAMPLE 326α-(4-Cyanobenzoyl)-oxy)-4,5α-epoxy-17-methyl-morphinan-7-en-3-olacetate

Example A

    ______________________________________                                        Haffner test in mice, ED.sub.50 values in nmol/kg i.v.                                    ED.sub.50 [nmol/kg]                                               Compound    10 min. 30 min.   60 min.                                                                             120 min.                                  ______________________________________                                        19           2      2.5       3.3   5.6                                         Morphine.HCl 17 19 21 37                                                    ______________________________________                                    

    ______________________________________                                        Haffner test in mice, ED.sub.50 values in nmol/kg p.o.                                    ED.sub.50 [nmol/kg]                                               Compound    30 min. 60 min.   120 min.                                                                             180 min.                                 ______________________________________                                        19           84     107       128    178                                        Morphine.HCl 279 296 539 718                                                ______________________________________                                    

7) 7,8-DIHYDROMORPHINE ESTERS EXAMPLE 14,5α-Epoxy-6α-(methoxyacetyl)-oxy)-3-methoxymethoxy-17-5methyl-morphinane

4,5α-Epoxy-6α-(methoxyacetyl)-oxy)-3-methoxymethoxy-17-methyl-morphinan-7-ene(0.59 g. 1.47 mmol) is dissolved in MeOH (30 ml), mixed with 10% Pd/C(0.47 g) and then agitated for 2 hours at ambient temperature under H₂(1 bar over pressure). The catalyst is eliminated by filtering through afilter compound and the filtrate is concentrated by rotaryconcentration.

Yield: 0.511 g (1.27 mmol, 86.2%)

¹³ C NMR (100 MHz CDCl₃) δ 169.2, 147.5, 138.4, 129.3, 127.3, 119.0,118.7, 95.9, 86.8, 69.0, 68.2, 59.6, 59.0, 56.1, 46.9, 42.3, 41.7, 40.6,35.9, 25.8, 20.3, 18.8.

Preparation of the starting compound:

4,5α-Epoxy-3-methoxymethoxy-17-methyl-morphinan-7-en-6α-ol

See Example 1 of "Ethers" above

4,5α-epoxy-6α-((methoxyacetyl)-oxy)-3-methoxymethoxy-17-methyl-morphinan-7-ene

4,5α-Epoxy-3-methoxymethoxy-17-methyl-morphinan-7-en-6α-ol (2.0 g, 6.1mmol) and 4-dimethylaminopyridine (0.8 g, 6.5 mmol) were dissolved inabsolute CH₂ Cl₂ (20 ml) and methoxy acetic acid (6.1 mmol) was addeddropwise whilst cooling with ice and the resulting mixture was stirredfor 2 hours at this temperature. The reaction mixture was poured ontowater (50 ml), the organic phase was washed twice more with 30 ml ofwater and dried over MgSO₄. The solvent was evaporated off and theresidue separated by flash chromatography (CH₂ Cl₂ /MeOH 9/1).

Yield: 2.4 g (99.6%).

EXAMPLE 2 4,5α-Epoxy-6α-(methoxyacetyl-oxy)-17-methyl-morphinan-3-olacetate

4,5α-epoxy-6α-(methoxyacetyl-oxy-17-methyl-morphinan (0.511 g 1.27 mmol)was mixed with H₂ O and glacial acetic acid 20 ml and stirred for 6hours at 100° C. The mixture was then concentrated at 40° C. using amotor vapour and the residue obtained was purified by flashchromatography (90 g silica gel; CH₂ Cl₂ /MeOH=9/1). The product wasdissolved in H₂ O (6 ml) and glacial acetic acid (0.6 ml) andlyophilised.

Yield: 0.33 g (0.79 mmol, 62.12%)

¹³ C NMR (100 MHz, CDCl₃) δ 175.9, 169.2, 145.1, 138.8, 127.2, 121.0,119.3, 117.9, 86.1, 68.8, 67.4, 60.3, 58.9, 47.3, 40.7, 40.5, 38.5,33.5, 26.1, 21.5, 20.9, 17.9.

EXAMPLE 34,5α-Epoxy-6α-((5-methoxycarbonyl-valeryl)-oxy)-3-methoxymethoxy-17-methyl-morphinane

4,5α-epoxy-6α-((5-methoxycarbonyl-valeryl)-oxy)-3-methoxymethoxy-17-methyl-morphinan-7-ene(0.48 g, 1.02 mmol) was dissolved in MeOH (30 ml), mixed with 10% Pd on0.35 g of activated charcoal and then agitated for 2 hours at ambienttemperature under H₂ (1 bar over pressure). The catalyst was illuminatedby filtering through a filter compound and the filtrate was concentratedby rotary evaporation.

Yield: 0.43 g (0.91 mmol, 89.2%).

¹³ C NMR (100 MHz, CDCl₃) δ 173.6, 171.9, 147.7, 138.9, 129.0, 126.1,119.1, 119.0, 95.9, 86.9, 67.6, 60.3, 56.2, 51.3, 47.4, 42.0, 41.3,39.9, 35.2, 33.5, 33.4, 25.9, 24.1, 23.8, 20.8, 18.6.

The starting compound was prepared using the method described in Example1.

EXAMPLE 44,5α-Epoxy-6α-((5-methoxycarbonyl-valeryl)-oxy)-17-methyl-morphinan-3-olacetate

4,5α-epoxy-6α-((5-methoxycarbonyl-valeryl)-oxy)-3-methoxymethoxy-17-methyl-morphinane(0.43 g, 0.91 mmol) was mixed with H₂ O (15 ml) and glacial acetic acid(15 ml) and stirred for 6 hours at 100° C. The mixture was thenevaporated down at 40° C. using a Rotavapor and the residue obtained waspurified by flash chromatography (60 g silical gel; CH₂ Cl₂ /MeOH=9/1).The product was dissolved in H₂ O (6 ml) and glacial acetic acid (0.6ml) and lyophilised. Yield: 0.221 g (0.45 mmol, 49.7%).

¹³ C NMR (100 MHz, CDCl₃) δ 174.3, 172.3, 145.4, 139.2, 127.3, 120.7,119.5, 118.2, 86.6, 67.2, 61.4, 51.6, 48.1, 41.2, 40.6, 38.5, 33.6,33.5, 29.6, 26.1, 24.2, 23.8, 21.4, 18.1.

Example A

                  TABLE 1                                                         ______________________________________                                        Haffner test in mice, ED.sub.50 values in nmol/kg, p.o.                                  ED.sub.50 [nmol/kg]                                                Compound   30 min. 60 min.   120 min.                                                                             180 min.                                  ______________________________________                                        2           55      71        89    207                                         4  39  44  73 189                                                             7,8-Dihydro- 177 195 250 481                                                  morphine.AcOH                                                                 Morphine.HCl 279 296 539 718                                                ______________________________________                                    

8) 7,8-DIHYDROMORPHINE ESTERS CONTAINING A CYCLIC GROUP EXAMPLE 14,5α-Epoxy-6α-(4-(4-methoxyphenyl)-butyryloxy)-17-methyl-morphinan-3-olacetate

4,5α-Epoxy-3-methoxymethoxy-17-methyl-morphinan-7-en-6α-ol

See Example 1 of "Ethers" above

4,5α-Epoxy-3-methoxymethoxy-6α-(4-(4-methoxyphenyl)-butyryloxy)-17-methyl-morphinan-7-ene

4,5α-Epoxy-3-methoxymethoxy-17-methyl-morphinan-7-en-6α-ol (2.64 g, 8mmol) and 4-(4-methoxyphenyl)-butyric acid (1.55 g, 8 mmol) aredissolved in CH₂ Cl₂ (30 ml) at 25° C. ThenN,N'-dicyclohexylcarbodiimide (1.65 g, 8 mmol) and4-dimethylaminopyridine (0.97 g, 8 mmol) are added to the stirredsolution. After the solution has been stirred for a further 14 hours at25° C. the precipitate is filtered oft and washed with CH₂ Cl₂ (20 ml).The combined organic phase is washed with water (2×10 ml), dried (Na₂SO₄), filtered and concentrated in the Rotavapor. The residue thusobtained is purified by flash chromatography (silica gel; mobile phase:CH₂ Cl₂ :MeOH=9:1). The residue is freed from residual solvent underhigh vacuum in order to obtain4,5α-epoxy-3-methoxymethoxy-6α-(4-(4-methoxyphenyl)-butyryloxy)-17-methyl-morphinan-7-ene(3.71 g, 91.7%)

4,5α-Epoxy-3-methoxymethoxy-6α-(4-(4-methoxyphenyl)-butyryloxy)-17-methyl-morphinane

A solution of4,5α-epoxy-3-methoxymethoxy-6α-(4-(4-methoxyphenyl)-butyryloxy)-17-methyl-morphinan-7-ene(1.01 g, 2 mmol) in MeOH (40 ml) is mixed with 10% Pd/C (650 mg) andagitated for 1.5 hours under 1 bar of H₂ pressure. The catalyst isremoved by filtering through Celite and the filtrate is evaporated down.The residue is pure4,5α-epoxy-3-methoxymethoxy-6α-(4-(4-methoxyphenyl)-butyryloxy)-17-methyl-morphinane(0.87 g, 85.7%).

¹³ C NMR (100 MHz, CDCl₃) δ 172.7, 158.2, 148.2, 139.0, 134.0, 129.6,119.3, 118.9, 114.1, 96.4, 87.7, 68.4, 60.2, 56.6, 55.6, 47.5, 43.0,42.4, 41.1, 36.7, 34.5, 33.8, 26.6, 25.9, 20.7, 19.5;

4,5α-Epoxy-6α-(4-(4-methoxyphenyl)-butyryloxy)-17-methyl-morphinan-3-olacetate

4,5α-Epoxy-3-methoxymethoxy-6α-(4-(4-methoxyphenyl)-butyryloxy)-17-methyl-morphinane(0.85 g, 1.67 mmol) is dissolved in water (35 ml) and glacial aceticacid (35 ml) and then stirred for 4 hours at 100° C. The volatilecomponents are eliminated using a Rotavapor. The residue thus obtainedis purified by flash chromatography (100 g silica gel; mobile phase:methylene chloride/methanol=7:1). The product is dissolved in a mixtureof water and glacial acetic acid and lyophilised.

Yield: 0.51 g4,5α-epoxy-6α-(4-(4-methoxyphenyl)-butyryloxy)-17-methyl-morphinan-3-olacetate (58.0%)

¹³ C NMR (100 MHz, CDCl₃) δ 176.0, 172.6, 157.9, 145.2, 138.3, 133.6,129.3, 128.3, 123.3, 119.4, 117.3, 113.8, 87.4, 67.6, 59.8, 55.3, 47.1,41.4, 39.6, 34.9, 34.1, 33.4, 26.2, 21.9, 20.8, 18.6.

The following compounds were prepared analogously:

EXAMPLE 24,5α-Epoxy-3-methoxymethoxy-6α-[4'-(4"-methoxyphenyl)-propylcarbonyl]oxy-17-methyl-morphine

C₃₀ H₃₇ NO₆

MW: 507.63 gmol⁻¹

¹³ C NMR (100 MHz, CDCl₃) δ 172.4, 157.9, 147.8, 138.7, 133.6, 129.3,119.0, 118.6, 113.7, 96.0, 87.4, 68.1, 59.8, 56.3, 55.3, 47.1, 42.7,40.8, 36.4, 34.2, 33.5, 26.3, 25.6, 20.4, 19.2.

EXAMPLE 34,5α-Epoxy-6α-[4'-(4"-Methoxyphenyl)propyl-carbonyl]oxy-17-methyl-morphin-3-olacetate

C₂₈ H₃₃ NO₅ AcOH=C₃₀ H₃₇ NO₇

MW: 523.63 gmol⁻¹

¹³ C NMR (100 MHz, CDCl₃) δ 176.0, 172.6, 157.9, 145.2, 138.3, 133.6,129.3, 128.0, 123.3, 119.4, 117.3, 113.8, 87.4, 67.6, 59.8, 55.3, 47.1,41.4, 39.6, 34.9, 34.1, 33.4, 26.2, 26.1, 21.9, 20.9, 18.6.

Example A

    ______________________________________                                        Haffner test in mice, ED.sub.50 values in nmol/kg i.v.                                     ED.sub.50 [nmol/kg]                                              Compound     10 min. 30 min.   60 min.                                                                             120 min.                                 ______________________________________                                        1            2.7     3.2       3.6    9                                         7,8-Dihydro- 16 23 32 130                                                     morphine.AcOH                                                                 Morphine.HCl 17 19 21  37                                                   ______________________________________                                    

    ______________________________________                                        Haffner test in mice, ED.sub.50 values in nmol/kg p.o.                                   ED.sub.50 [nmol/kg]                                                Compound   30 min.  60 min.  120 min.                                                                              180 min.                                 ______________________________________                                        1           65       74      136     195                                        7,8-Dihydro- 177 195 250 481                                                  morphine.AcOH                                                                 Morphine.HCl 279 296 539 718                                                ______________________________________                                    

9) CARBAMATES EXAMPLE 14,5α-Epoxy-6α-((N-ethyloxycarbonylmethyl-carbamoyl)-oxy)-3-methoxymethoxy-17-methyl-morphinan-7-ene

4,5α-Epoxy-3-methoxymethoxy-17-methyl-morphinan-7-en-6α-ol (5.27 g, 16mmol) is dissolved in absolute DMF (16 ml) and mixed withethylisocyanato acetate (10.33 g, 80 mmol) with stirring. After 5 hoursthe reaction mixture is poured onto water (150 ml) and extracted 3× withmethylene chloride (50 ml). The combined organic phases are dried oversodium sulphate and filtered and the filtrate is evaporated down in aRotavapor. The residue thus obtained is purified by flash chromatography(silica gel; methylene chloride:methanol =9:1).

Yield: (6.68 g, 91%)4,5α-epoxy-6α-((N-ethyloxycarbonyl-methylcarbamoyl)-oxy)-3-methoxymethoxy-17-methyl-morphinan-7-ene

¹³ C NMR (100 MHz, CDCl₃) δ 169.0, 161.7, 155.0, 147.1, 137.9, 130.4,129.7, 128.6, 128.4, 127.9, 118.4, 117.7, 95.1, 88.3, 70.0, 68.1, 60.5,58.1, 55.4, 45.7, 42.18, 42.0, 39.9, 34.5, 19.8.

Starting compound: see Example 1 of "Ethers" above

EXAMPLE 24,5-Epoxy-6α-((N-ethyloxycarbonylmethyl-carbamoyl)-oxy)-17-methyl-morphinan-7-en-3-olacetate

4,5α-Epoxy-6α-((N-ethyloxycarbonylmethyl-carbamoyl)oxy)-3-methoxymethoxy-17-methyl-morphinan-7-ene(2 g, 4.36 mmol) is dissolved in water (60 ml) and glacial acetic acid(60 ml) and then stirred for 6 hours at 100° C. The volatileconstituents are eliminated using a Rotavapor. The residue thus obtainedis purified by flash chromatography (90 g silica gel; mobile phase:methylene chloride/methanol=9:1).

Yield: (0.95 g, 46%)4,5α-epoxy-6α-((N-ethyloxy-carbonylmethylcarbamoyl)-oxy)-17-methyl-morphinan-7-en-3-ol

¹³ C NMR (100 MHz, CDCl₃) δ 176.0, 171.3, 156.0, 138.6, 129.1, 128.5,127.9, 123.5, 119.6, 116.8, 87.2, 66.9, 61.7, 59.0, 46.6, 42.2, 42.5,40.9, 38.5, 33.4, 21.9, 20.5, 13.7.

The following were prepared analogously:

EXAMPLE 34,5α-Epoxy-6α-((N-ethyloxycarbonylethyl-carbamoyl)-oxy)-17-methyl-morphinan-7-en-3-olacetate EXAMPLE 44,5α-Epoxy-6α-(N-hydroxyethyl-carbamoyl)-oxy)-17-methyl-morphinan-7-en-3-olacetate

Example A

                  TABLE 1                                                         ______________________________________                                        Haffner test in mice, ED.sub.50 values in nmol/kg, p.o.                         Compound                                                                      according to ED.sub.50 [nmol/kg]                                            Example   30 min. 60 min.    120 min.                                                                             180 min.                                  ______________________________________                                        2          77      91        106    147                                         Morphine.HCl 279 296 539 718                                                ______________________________________                                    

10) 7,8-DIHYDROMORPHINE CARBAMATES EXAMPLE 14,5α-Epoxy-6α-((N-ethyloxycarbonylmethyl-carbamoyl)-oxy)-3-methoxymethoxy-17-methyl-morphinane

A solution of4,5α-epoxy-6α-((N-ethyloxycarbonylmethyl-carbamoyl)-oxy)-3-methoxymethoxy-17-methyl-morphinan-7-ene(1.15 g, 2.5 mmol) in methanol (50 ml) is hydrogenated with 10% Pd onactivated charcoal (800 mg) at RT under 1 bar of hydrogen for 2 hours.After the reaction time has expired the resulting mixture is filteredthrough a filter compound, washed with methanol and concentrated byrotary evaporation.

Yield:4,5α-epoxy-6α-((N-ethyloxycarbonylmethyl-carbamoyl)-oxy)-3-methoxymethoxy-17-methyl-morphinane(1.00 g, 86.9%).

¹³ C NMR (100 MHz, CDCl₃) δ 170.2, 156.0, 148.3, 138.4, 130.3, 128.6,119.4, 119.2, 96.1, 88.2, 69.9, 61.5, 60.1, 59.9, 56.4, 50.8, 47.2,43.0, 42.5, 41.0, 36.9, 25.7, 20.6, 19.4, 14.4.

Starting compound: see Example 1 of "Carbamates" above

EXAMPLE 24,5α-Epoxy-6α-((N-ethyloxycarbonylmethyl-carbamoyl)-oxy)-17-methyl-morphinan-3-olacetate

4,5α-Epoxy-6α-((N-ethyloxycarbonylmethyl-carbamoyl)-oxy)-3-methoxymethoxy-17-methyl-morphinane(0.9994 g, 2.17 mnol) is dissolved in H₂ O (30 ml) and glacial aceticacid (30 ml) and stirred for 6 hours at 100° C. The reaction solution isconcentrated in a Rotavapor at 40° C. The residue is purified by flashchromatography (90 g silica gel, mobile phase=CH₂ Cl₂ /MeOH=9/1).

Yield:4,5α-Epoxy-6α-((N-ethyloxycarbonylmethyl-carbamoyl)-oxy)-17-methyl-morphinan-3-olacetate (805 mg, 77.9%)

¹³ C NMR (100 MHz, CDCl₃) δ 176.4, 170.9, 155.9, 145.7, 138.8, 128.0,122.2, 119.5, 118.5, 87.3, 68.6, 61.8, 60.1, 47.2, 42.8, 41.0, 39.0,34.2, 26.4, 22.1, 21.1, 18.6, 14.1.

The following compound was prepared analogously:

EXAMPLE 34,5α-Epoxy-6α-((N-ethyloxycarbonylethyl-carbamoyl)-oxy)-17-methyl-morphinan-3-olacetate

Example A

                  TABLE 1                                                         ______________________________________                                        Haffner test in mice, ED.sub.50 values in nmol/kg, p.o.                                  ED.sub.50 [nmol/kg]                                                Compound   30 min. 60 min.   120 min.                                                                             180 min.                                  ______________________________________                                        2           24      33        52    118                                         7,8-Dihydro- 177 195 250 481                                                  morphine.AcOH                                                                 Morphine.HCl 279 296 539 718                                                ______________________________________                                    

11) FURTHER ETHERS CONTAINING A CYCLIC GROUP EXAMPLE 14,5α-Epoxy-17-methyl-6α-((2-pyridyl)-oxy)-morphinan-7-en-3-ol acetate

4,5α-Epoxy-3-methoxymethoxy-17-methyl-morphinan-7-en-6α-ol

See Example 1 of "Ethers" above.

4,5α-Epoxy-3-methoxymethoxy-17-methyl-6α-((2-pyridyl)-oxy)-morphinan-7-ene

NaH (0.432 g, 18 mmol) is stirred with absolute DMF (12 ml) at ambienttemperature and then4,5α-epoxy-3-methoxymethoxy-17-methyl-morphinan-7-en-6α-ol (1.9764 g, 6mmol) in DMF (12 ml) is added. After the development of gas has ceased,a solution of 2-bromopyridine in absolute DMF (8 ml) is added at RT.After 3 hours at RT this reaction mixture is poured onto H₂ O (100 ml)and extracted 3 times with CH₂ Cl₂ (60 ml). The combined organic phasesare dried with Ha₂ SO₄, concentrated by rotary evaporation and theresidue is purified by flash chromatography (90 g silica gel, CH₂ Cl₂/MeOH=9/1).

Yield: 1.00 g (2.46 mmol, 41%).

¹³ C NMR (100 MHz, CDCl₃) δ 162.7, 148.3, 146.6, 138.6, 131.4, 130.0,128.9, 119.0, 118.9, 118.6, 117.0, 111.5, 96.1, 96.0, 89.2, 69.0, 59.1,56.2, 46.6, 43.1, 40.8, 35.5, 20.6.

4,5α-Epoxy-17-methyl-6α-((2-pyridyl)-oxy)-morphinan-7-en-3-ol acetate

4,5α-Epoxy-3-methoxymethoxy-17-methyl-6α-((2-pyridyl)-oxy)-morphinan-7-ene(0.54 g, 1.33 mmol) is mixed with H₂ O (20 ml) and glacial acetic acid(20 ml) and stirred for 2.5 hours at 100° C. The mixture is thenconcentrated by rotary evaporation in a Rotavapor at 40° C. and theresidu e obtained is purified by flash chromatography (90 g silica gel;CH₂ Cl₂ /MeOH=9/1). The product is dissolved in H₂ O (7 ml) and glacialacetic acid (0.7 ml) and lyophilised. Yield: 0.436 g (1.03 mmol, 77.6%)

¹³ C NMR (100 MHz, CDCl₃) δ 176.8, 162.9, 147.2, 139.4, 139.2, 131.1,129.8, 127.4, 123.7, 119.9, 117.7, 117.6, 111.7,89.1, 69.2, 59.4, 46.7,42.8, 41.7, 38.9, 33.9, 22.5, 21.7.

EXAMPLE 24,5α-Epoxy-6α-((5-(ethyloxycarbonyl)-2-pyridyl)-oxy)-17-methyl-morphinan-7-en-3-olacetate

4,5α-Epoxy-6α-((5-(ethyloxycarbonyl)-2-pyridyl)-oxy)-3-methoxymethoxy-17-methyl-morphinan-7-ene

NaH (0.72 g, 30 mmol) is stirred with absolute DMF (12 ml) at RT andthen 4,5α-epoxy-3-methoxymethoxy-17-methyl-morphinan-7-en-6α-ol (1.9764g, 6 mmol) in DMF (12 ml) is added. After the development of gas hasceased, a solution of ethyl 2-chloro-nicotinate (5.568 g, 30 mmol) inabsolute DMF (8 ml) is added at RT. After 1 hour at RT this reactionmixture is poured onto H₂ O (100 ml) and extracted 3 times with CH₂ Cl₂(60 ml). The combined organic phases are dried with Na₂ SO₄,concentrated by rotary evaporation and the residue is purified by flashchromatography (90 g silica gel, CH₂ Cl₂ MeOH=9/1). Yield: 2.53 g (5.29mmol, 88%)

¹³ C NMR (100 MHz, CDCl₃) δ 165.7, 165.6, 150.0, 148.4, 140.0, 139.1,131.6, 129.7, 129.1, 120.6, 119.5, 118.9, 111.3, 96.3, 89 .1, 70.1,61.2, 59.4, 46.9, 4 3.4, 43.3, 41.1, 35.8, 20.9, 14.6.

4,5α-Epoxy-17-methyl-6α-((5-(ethyloxycarbonyl)-2-pyridyl)-oxy)-17-methyl-morphinan-7-en-3-ol acetate

4,5α-Epoxy-6α-((5-(ethyloxycarbonyl)-2-pyridyl)-oxy)-3-5methoxymethoxy-17-methyl-morphinan-7-ene (0.957 g, 2 mmol): is mixedwith H₂ O (30 ml) and glacial acetic acid (30 ml) and stirred for 6hours at 100° C. The mixture is then concentrated at 40° C. using aRotavapor and the residue obtained is purified by flash chromatography(90 g silica gel; CH₂ Cl₂ /MeOH=9/1). The product is dissolved in H₂ O(6 ml) and glacial acetic acid (0.6 ml) and lyophilised. Yield: 0.70 g(1.42 mmol, 70.8%)

¹³ C NMR (100 MHz, CDCl₃) δ 176.4, 165.3, 149.7, 139.9, 138.8, 129.9,129.6, 127.9, 124.1, 120.5, 119.6, 117.2, 110.9, 88.6, 69.6, 61.0, 59.0,46.4, 42.6, 41.7, 38.9, 33.9, 22.1, 21.2, 14.3.

The following compounds were prepared analogously:

EXAMPLE 34,5α-Epoxy-3-methoxymethoxy-6α-[2'-pyridyl]oxy-17-methyl-morphin-7-ene

C₂₇ H₃₀ N₂ O₆

MW:478.55 gmol⁻¹

¹³ C NMR (100 MHz, CDCl₃) δ 165.4, 165.3, 149.7, 148.1, 139.6, 138.8,131.2, 129.3, 129.2, 128.8, 120.2, 119.1, 118.6, 111.0, 96.0, 88.8,69.8, 60.8, 59.0, 56.2, 46.3, 43.0, 42.9, 40.8, 35.4, 20.5, 14.3.

EXAMPLE 4 4,5α-Epoxy-6α-[2'-pyridyl]oxy-17-methyl-morphin-7-en-3-olacetate

C₂₅ H₂₆ N₂ O₅ AcOH=C₂₇ H₃₀ N₂ O₇

MW:494.55 gmol⁻¹

¹³ C NMR (100 MHz, CDCl₃) δ 176.4, 165.3, 149.7, 145.6, 139.9, 138.8,129.9, 129.6, 127.9, 124.1, 120.5, 119.6, 117.2, 110.9, 88.6, 69.6,61.0, 59.0, 46.4, 42.6, 41.7, 38.9, 33.9, 22.1, 21.2, 14.3.

EXAMPLE 54,5α-Epoxy-3-methoxymethoxy-6α-[2-pyrazinyl]oxy-17-methyl-morphin-7-ene

C₂₃ H₂₅ N₃ O₄

MW:407.45 gmol⁻¹

¹³ C NMR (100 MHz, CDCl₃) δ 159.2, 148.0, 140.3, 138.9, 136.9, 136.3,131.1, 129.5, 129.1, 128.7, 119.3, 118.5, 95.9, 88.4, 69.6, 59.1, 56.2,46.6, 43.1, 43.0, 40.8, 35.5, 20.6.

EXAMPLE 6 4,5α-Epoxy-6α-[2-pyrazinyl]oxy-17-methyl-morphin-7-en-3-olacetate

C₂₃ H₂₅ N₃ O₅

MW:423.47 gmol⁻¹

¹³ C NMR (100 MHz, CDCl₃) δ 176.1, 159.3, 145.3, 140.5, 139.2, 136.3,135.4, 129.6, 129.4, 128.1, 123.7, 119.9, 117.3, 87.7, 69.1, 59.1, 46.6,42.2, 41.8, 39.0, 34.0, 22.1, 20.9.

EXAMPLE 76α-[2-Quinolinyl]oxy-4,5α-epoxy-3-methoxymethoxy-17-methyl-morphin-7-ene

C₂₈ H₂₈ N₂ O₄

MW:456.52 gmol⁻¹

¹³ C NMR (100 MHz, CDCl₃) δ 160.9, 148.4, 146.4, 138.9, 131.5, 130.1,129.4, 128.9, 127.4, 127.3, 125.3, 124.1, 119.1, 118.7, 113.3, 96.1,89.1, 69.1, 59.2, 56.3, 46.7, 43.1, 43.0, 40.9, 35.6, 20.7.

EXAMPLE 8 6α-[2-Quinolinyl]oxy-4,5α-epoxy-17-methyl-morphin-7-en-3-olacetate

C₂₈ H₂₈ N₂ O₅

MW:472.52 gmol⁻¹

¹³ C NMR (100 MHz, CDCl₃) δ 176.3, 160.8, 146.3, 145.6, 139.1, 138.8,130.7, 129.6, 129.5, 127.4, 127.3, 127.2, 125.3, 124.3, 123.8, 119.6,117.2, 113.0, 88.7, 68.7, 59.1, 46.5, 42.4, 41.5, 38.8, 33.9, 22.0,21.2.

EXAMPLE 94,5α-Epoxy-3-methoxymethoxy-17-methyl-6α-[2-pyrimidinyl]oxy-morphin-7-ene

C₂₃ H₂₅ N₃ O₄

MW:407.47 gmol⁻¹

¹³ C NMR (100 MHz, CDCl₃) δ 164.4, 159.2, 148.2, 139.1, 131.1, 129.4,129.1, 128.6, 119.2, 118.7, 115.2, 96.2, 88.5, 71.0, 59.1, 56.3, 46.6,43.1, 40.9, 35.6, 20.6.

EXAMPLE 10 4,5α-Epoxy-17-methyl-6α-[2-pyrimidinyl]oxy-morphin-7-en-3-olacetate

C₂₃ H₂₅ N₃ O₅

MW:423.47 gmol⁻¹

¹³ C NMR (100 MHz, CDCl₃) δ 175.9, 164.3, 159.4, 145.9, 139.0, 129.6,129.5, 128.1, 124.3, 119.8, 117.6, 115.5, 88.3, 70.7, 59.1, 46.5, 42.6,41.9, 39.3, 34.1, 22.0, 21.1.

EXAMPLE 114,5α-Epoxy-3-methoxymethoxy-17-methyl-6α-(6'-methyl-2'-pyridyl)oxy-morphin-7-ene

C₂₅ H₂₈ N₂ O₄

MW:420.51 gmol⁻¹

¹³ C NMR (100 MHz, CDCl₃) δ 162.1, 155.9, 148.4, 138.8, 131.5, 130.4,128.8, 128.5, 119.0, 118.7, 115.9, 107.9, 96.1, 89.3, 68.6, 59.2, 56.3,46.7, 43.1, 43.0, 40.9, 35.6, 24.2, 20.7.

EXAMPLE 124,5α-Epoxy-17-methyl-6α-(6'-methyl-2'-pyridyl)oxy-morphin-7-en-3-olacetate

C₂₅ H₂₈ N₂ O₅

MW:436.51 gmol⁻¹

¹³ C NMR (100 MHz, CDCl₃) δ 175.0, 162.0, 156.2, 145.7, 139.1, 138.7,130.9, 129.7, 127.2, 124.2, 119.5, 117.1, 116.2, 107.7,89.2, 68.5, 59.2,46.6, 42.6, 41.9, 39.2, 34.1, 24.2, 22.0, 21.2.

EXAMPLE 134,5α-Epoxy-6α-(3'-ethoxycarbonyl-pyrid-2-yl)oxy-3-methoxymethoxy-17-methyl-morphin-7-ene

C₂₇ H₃₀ N₂ O₆

MW:478.55 gmol⁻¹

¹³ C NMR (100 MHz, CDCl₃) δ 165.3, 160.9, 150.2, 148.3, 141.2, 138.9,131.4, 129.8, 128.8, 119.1, 119.0, 116.6, 114.9, 96.2, 88.9, 70.2, 61.0,59.1, 56.2, 46.7, 43.1, 43.0, 40.9, 35.6, 20.6, 14.1.

EXAMPLE 144,5α-Epoxy-6α(3'-ethoxycarbonyl-pyrid-2-yl)oxy-17-methyl-morphin-7-en-3-olacetate

C₂₇ H₃₀ N₂ O₇

MW:494.55 gmol⁻¹

¹³ C NMR (100 MHz, CDCl₃) δ 176.3, 165.4, 160.5, 150.1, 146.1, 140.8,139.3, 130.5, 129.3, 126.5, 123.1, 119.7, 118.1, 116.8, 115.0, 87.9,68.8, 61.4, 59.2, 46.5, 41.8, 41.1, 38.0, 33.0, 22.0, 21.4, 14.1.

EXAMPLE 154,5α-Epoxy-3-methoxymethoxy-6α-(6'-methoxy-2'-pyridyl)oxy-17-methyl-morphin-7-ene

C₂₅ H₂₈ N₂ O₅

MW:436.51 gmol⁻¹

¹³ C NMR (100 MHz, CDCl₃) δ 162.9, 161.6, 148.5, 141.1, 138.8, 131.3,130.0, 128.8, 128.7, 119.1, 118.7, 102.2, 101.2, 96.1, 89.6, 69.4, 59.1,56.3, 53.3, 46.6, 43.2, 43.1, 41.1, 35.8, 20.6.

EXAMPLE 164,5α-Epoxy-6α-(6'-methoxy-2'-pyridyl)oxy-17-methyl-morphin-7-en-3-olacetate

C₂₅ H₂₈ N₂ O₆

MW:452.51 gmol⁻¹

¹³ C NMR (100 MHz, CDCl₃) δ 176.2, 163.0, 161.5, 145.6, 141.3, 13.8,130.7, 129.4, 127.0, 123.8, 119.7, 117.2, 101.8, 101.6, 89.3, 68.7,59.2, 53.5, 46.6, 42.2, 41.6, 38.8, 21.8, 21.3.

EXAMPLE 174,5α-Epoxy-6α-(6-ethoxycarbonyl-2-pyridyl)oxy-3-methoxymethoxy-17-methyl-morphin-7-ene

C₂₇ H₃₀ N₂ O₆

MW: 478.55 gmol⁻¹

¹³ C NMR (100 MHz, CDCl₃) δ 165.0, 162.3, 148.5, 145.5, 139.2, 138.8,131.5, 129.7, 129.0, 128.9, 119.1, 118.7, 118.6, 115.4, 96.1, 88.8,69.6, 61.4, 59.2, 56.3, 46.7, 43.1, 43.0, 40.8, 35.6, 20.6, 14.3.

EXAMPLE 184,5α-Epoxy-6α-(6-ethoxycarbonyl-2-pyridyl)oxy-17-methyl-morphin-7-en-3-olacetate

C₂₇ H₃₀ N₂ O₇

MW: 494.55 gmol⁻¹

¹³ C NMR (100 MHz, CDCl₃) δ 176.2, 165.0, 162.3, 145.6, 145.5, 139.5,138.8, 130.4, 129.5, 127.2, 123.7, 119.7, 118.9, 117.2, 115.2, 88.5,61.6, 59.2, 46.5, 42.3, 41.5, 38.6, 33.6, 21.9, 21.4, 14.3.

EXAMPLE 195α,6α-7,8-Didehydro-4,5-epoxy-3-methoxymethoxy-17-methyl-6-[3-(trifluoromethyl)-2-pyridyl]oxy-morphinane

C₂₅ H₂₅ F₃ N₂ O₄

MW: 474.48 gmol⁻¹

¹³ C NMR (100 MHz, CDCl₃) δ 159.2, 150.0, 147.8, 139.0, 136.4, 136.3,136.2, 130.9, 129.1, 129.0, 128.3, 124.0, 121.4, 119.0, 118.2, 116.1,113.6, 113.2, 112.9, 112.6, 95.7,88.4, 70.1, 58.8, 55.8, 46.3, 42.9,42.8, 40.6, 35.4, 20.3.

EXAMPLE 205α,6α-7,8-Didehydro-4,5-epoxy-17-methyl-6-[3-(trifluoromethyl)-2-pyridyl]oxy-morphinan-3-olacetate

C₂₅ H₂₅ F3N₂ O₅

MW: 490.48 gmol⁻¹

¹³ C NMR (100 MHz, CDCl₃) δ 176.6, 159.3, 150.3, 145.6, 139.3, 136.7,136.6, 130.2, 129.3, 127.1, 124.2, 123.2, 121.5, 119.6, 117.3, 116.5,113.4, 113.1, 87.9, 69.5, 59.2, 46.5, 42.2, 41.3, 38.4, 33.5, 22.2,21.2.

EXAMPLE 21(5α,6α)-7,8-Didehydro-4,5-epoxy-3-methoxymethoxy-17-methyl-6-[5-(trifluoromethyl)-2-pyridyl]oxy-morphinane

C₂₅ H₂₅ F₃ N₂ C₄

MW: 490.48 gmol⁻¹

¹³ C NMR (100 MHz, CDCl₃) δ 164.6, 147.9, 144.6, 144.5, 138.7, 135.6,131.0, 129.1, 129.0 128.6, 125.2, 122.5, 120.6, 120.2, 119.9, 119.6,119.1, 118.4, 111.3, 95.8, 88.4, 69.7, 58.9, 56.0, 46.4, 42.8, 40.6,35.3, 20.3.

EXAMPLE 22(5α,6α)-7,8-Didehydro-4,5-epoxy-17-methyl-6-[5-(trifluoromethyl)-2-pyridyl]oxy-morphinan-3-olacetate

C₂₅ H₂₅ F₃ N₂ O₅

MW: 490.48 gmol⁻¹

¹³ C NMR (100 MHz, CDCl₃) δ 176.7, 164.6, 145.7, 144.7, 139.3, 136.0,130.1, 129.2, 127.3, 125.3, 123.0, 122.6, 120.7, 120.4, 119.7, 117.6,111.5, 881, 69.5, 59.2, 46.5, 42.2, 41.3, 38.3, 33.4, 22.1, 21.4.

EXAMPLE 23(5α,6α)-6-(3-Cyano-2-pyridyl)oxy-7,8-didehydro-4,5-epoxy-3-methoxymethoxy-17-methyl-morphinane

C₂₅ H₂₅ N₃ O₄

MW: 431.50 gmol⁻¹

¹³ C NMR (100 MHz, CDCl₃) δ 162.8, 151.0, 147.8, 143.2, 139.3, 130.9,129.4, 128.9, 128.4, 119.4, 118.2, 1116.8, 114.8, 97.1, 96.1, 88.1,70.6, 59.1, 56.3, 46.6, 43.1, 42.9, 40.8, 35.5, 20.5.

EXAMPLE 24(5α,6α)-6-(3-Cyano-2-pyridyl)oxy-7,8-didehydro-4,5-epoxy-17-methyl-morphinan-3-olacetate

C₂₅ H₂₅ N₃ O₅

MW: 447.50 gmol⁻¹

¹³ C NMR (100 MHz, CDCl₃) δ 176.6, 162.8, 151.1, 145.7, 143.2, 139.5,129.7, 129.1, 127.4, 122.9, 119.7, 117.7, 117.1, 115.1, 97.1, 87.6,70.3, 59.2, 46.5, 42.0, 41.3, 38.2, 33.3, 22.1, 21.3.

EXAMPLE 25(5α,6α)-6-(4-Cyano-2-pyridyl)oxy-7,8-didehydro-4,5-epoxy-3-methoxymethoxy-17-methyl-morphinane

C₂₅ H₂₅ N₃ O₄

MW: 431.50 gmol⁻¹

¹³ C NMR (100 MHz, CDCl₃) δ 162.8, 148.1, 147.8, 138.8, 131.0, 129.3,128.9, 128.5, 122.5, 119.2, 118.2, 117.8, 116.2, 114.4, 95.7,88.3, 69.8,59.0, 56.1, 46.5, 42.9, 42.8, 10.6, 35.3, 20.4.

EXAMPLE 26(5α,6α)-6-(4-Cyano-2-pyridyl)oxy-7,8-didehydro-4,5-epoxy-17-methyl-morphinan-3-olacetate

C₂₅ H₂₅ N₃ O₅

MW: 447.50 gmol⁻¹

¹³ C NMR (100 MHz, CDCl₃) δ 176.5, 162.7, 148.1, 145.4, 139.1, 129.9,129.1, 127.5, 123.0, 122.7, 119.9, 118.2, 117.6, 116.3, 114.4, 88.1,69.4, 59.2, 46.5, 42.2, 41.2, 38.2, 33.3, 21.9, 21.4.

EXAMPLE 274α,5α-Epoxy-3-methoxymethoxy-17-methyl-6α-[5-pyrrolidinylcarbamoyl-)-2-pyridyl]oxy-morphin-7-ene

C₂₉ H₃₃ N₃ O₅

MW: 503.60 gmol⁻¹

¹³ C NMR (100 MHz, CDCl₃) δ 167.2, 163.4, 148.2, 146.2, 138.7, 138.4,131.3, 129.5, 129.1, 128.8, 126.4, 119.1, 118.6, 111.0, 96.0, 88.9,69.6, 59.0, 56.2, 49.7, 46.5, 46.4, 43.0, 40.8, 35.5, 26.5, 24.3, 20.6.

EXAMPLE 284α,5α-Epoxy-17-methyl-6α-[5-pyrrolidinylcarbamoyl-)-2-pyridyl]oxy-morphin-7-en-3-olacetate

C₂₉ H₃₃ N₃ O₆

MW: 519.60 gmol⁻¹

¹³ C NMR (100 MHz, CDCl₃) δ 176.3, 167.3, 163.3, 146.1, 145.8, 139.2,138.6, 130.2, 129.3, 127.4, 126.4, 123.2, 119.5, 117.5, 111.0, 88.3,69.3, 59.1, 49.7, 46.5, 46.4, 42.3, 41.4, 38.5, 33.6, 26.4, 24.3, 22.1,21.3.

EXAMPLE 294α,5α-Epoxy-3-methoxymethoxy-17-methyl-6α-[3-pyrrolidinylcarbamoyl)-2-pyridyl]oxy-morphin-7-ene

C₂₉ H₃₃ N₃ O₅

MW: 503.60 gmol⁻¹

¹³ C NMR (100 MHz, CDCl₃) δ 165.6, 157.9, 148.5, 147.6, 138.8, 137.9,131.3, 129.7, 129.2, 128.9, 121.7, 118.9, 118.4, 117.2, 96.1, 89.5,70.7, 58.8, 56.2, 47.4, 46.4, 45.7, 43.5, 43.0, 41.0, 35.8, 25.9, 24.3,20.6.

EXAMPLE 304α,5α-Epoxy-17-methyl-6α-[3-pyrrolidinylcarbamoyl)-2-pyridyl]oxy-morphin-7-en-3-olacetate

C₂₉ H₃₃ N₃ O₆

MW: 519.60 gmol⁻¹

¹³ C NMR (100 MHz, CDCl₃) δ 176.2, 166.6, 157.7, 147.8, 145.9, 139.6,137.1, 130.4, 129.0, 126.6, 122.2, 121.7, 119.6, 118.9, 117.9, 87.0,68.7, 59.3, 47.8, 46.5, 45.8, 41.4, 41.0, 37.8, 32.9, 25.7, 24.3, 21.8,21.4.

EXAMPLE 316α-[5-(Dimethylcarbamoyl-)-2-pyridyl]oxy-4,5α-epoxy-3-methoxymethoxy-17-methyl-morphin-7-ene

C₂₇ H₃₁ N₃ O₅

MW: 477.57 gmol⁻¹

¹³ C NMR (100 MHz, CDCl₃) δ 169.2, 163.3, 148.2, 146.1, 138.7, 138.3,131.3, 129.5, 129.1, 128.8, 125.4, 119.1, 118.6, 111.1, 96.0, 88.9,69.6, 59.0, 56.2, 46.5, 43.0, 42.9, 40.7, 35.4, 20.6.

EXAMPLE 326α-[5-(Dimethylcarbamoyl-)-2-pyridyl]oxy-4,5α-epoxy-17-methyl-morphin-7-en-3-olacetate

C₂₇ H₃₁ N₃ O₆

MW: 493.57 gmol⁻¹

¹³ C NMR (100 MHz, CDCl₃) δ 176.3, 169.4, 163.2, 145.9, 145.7, 139.3,138.5, 130.5, 129.0, 126.8, 125.4, 122.5, 119.6, 117.6, 111.0, 88.2,69.0, 59.3, 46.5, 42.0, 41.0, 38.0, 33.1, 21.7, 21.6.

EXAMPLE 334α,5α-Epoxy-3-methoxymethoxy-17-methyl-6α-[4(pyrrolidinylcarbamoyl-)-2-pyridyl]oxy-morphin-7-ene

C₂₉ H₃₃ N₃ O₅

MW: 503.60 gmol⁻¹

¹³ C NMR (100 MHz, CDCl₃) δ 167.1, 162.9, 148.3, 147.6, 147.2, 138.8,131.3, 129.7, 129.1, 128.8, 119.1, 118.6, 114.8, 109.2, 96.0, 89.1,69.6, 59.0, 56.3, 49.1, 46.6, 46.0, 43.1, 40.8, 35.5, 26.2, 24.3, 20.6.

EXAMPLE 344α,5α-Epoxy-17-methyl-6α-[4(pyrrolidinylcarbamoyl-)-2-pyridyl]oxy-morphin-7-en-3-olacetate

C₂₇ H₃₃ N₃ O₆

MW: 519.60 gmol⁻¹

¹³ C NMR (100 MHz, CDCl₃) δ 176.2, 167.1, 162.7, 147.5, 147.2, 145.7,139.1, 130.3, 129.4, 127.5, 13.4, 119.6, 117.4, 114.9, 109.2, 88.4,69.2, 59.1, 49.1, 46.4, 46.1, 42.4, 41.5, 38.6, 33.7, 26.2, 24.3, 22.1,21.3.

EXAMPLE 356α-[4-(Dimethylcarbamoyl-)-2-pyridyl]oxy-4,5α-epoxy-3-methoxymethoxy-17-methyl-morphin-7-ene

C₂₇ H₃₁ N₃ O₅

MW: 477.57 gmol⁻¹

¹³ C NMR (100 MHz, CDCl₃) δ 168.9, 162.9, 148.2, 147.3, 146.9, 138.8,131.3, 129.7, 129.1, 128.8, 119.1, 118.6, 114.8, 109.2, 96.0, 89.1,69.6, 59.0, 56.2, 46.6, 43.1, 43.0, 40.8, 39.0, 35.5, 35.1, 20.6.

EXAMPLE 366α-[4-(Dimethylcarbamoyl-)-2-pyridyl]oxy-4,5α-epoxy-17-methyl-morphin-7-en-3-olacetate

C₂₇ H₃₁ N₃ O₆

MW: 493.57 gmol⁻¹

¹³ C NMR (100 MHz, CDCl₃) δ 176.3, 169.1, 162.7, 147.3, 146.8, 145.7,139.3, 130.6, 129.1, 126.8, 122.6,119.7, 117.6, 114.9, 109.2, 88.1,69.0, 59.3, 46.5, 42.1, 41.1, 39.1, 38.1, 35.1, 33.2, 21.8, 21.5.

EXAMPLE 376α-[(5-Cyano-2-pyridyl)oxy-4,5α-epoxy-3-methoxymethoxy-17-methyl-morphin-7-ene

C₂₅ H₂₅ N₃ O₄

MW: 431.50 gmol⁻¹

¹³ C NMR (100 MHz, CDCl₃) δ 164.7, 151.7, 147.9, 141.1, 138.8, 131.1,129.6, 128.7, 119.3, 118.5, 117.1, 112.1, 102.8, 95.9, 88.4, 70.2, 59.0,56.2, 46.6, 43.0, 42.9, 40.7, 35.4, 20.5.

EXAMPLE 386α-[(5-Cyano-2-pyridyl)oxy-4,5α-epoxy-17-methyl-morphin-7-en-3-olacetate

C₂₅ H₂₅ N₃ O₅

MW: 447.50 gmol⁻¹

¹³ C NMR (100 MHz, CDCl₃) δ 176.6, 164.5, 151.6, 145., 141.4, 139.2,129.9, 129.0, 127.1, 122.6, 119.9, 117.6, 117.0, 112.1, 103.00, 87.8,69.5, 59.3, 46.6, 41.9, 41.0, 37.9, 33.0, 21.7, 21.5.

EXAMPLE 396α-[3-(Dimethylcarbamoyl-)-2-pyridyl]oxy-4,5α-epoxy-3-methoxymethoxy-17-methyl-morphin-7-ene

C₂₇ H₃₁ N₃ O₅

MW: 477.57 gmol⁻¹

¹³ C NMR (100 MHz, CDCl₃) δ 167.5, 157.7, 147.7, 138.9, 138.2, 131.3,129.7, 129.2, 128.8, 120.6, 119.0, 117.3, 96.0, 89.4, 70.4, 58.9, 56.2,50.6, 46.4, 43.4, 43.1, 40.8, 38.4, 35.7, 34.9, 20.6.

EXAMPLE 406α-[3-(Dimethylcarbamoyl)-2-pyridyl]oxy-4,5α-epoxy-17-methyl-morphin-7-en-3-olacetate

C₂₇ H₃₁ N₃ O₆

MW: 493.57 gmol⁻¹

¹³ C NMR (100 MHz, CDCl₃) δ 176.2, 157.8, 147.8, 139.5, 137.3, 130.4,129.2, 126.9, 122.7, 120.9, 119.7, 118.0, 87.1, 68.6, 59.3, 46.5, 41.2,38.4, 38.0, 35.1, 33.1, 21.8, 21.4.

EXAMPLE 414,5α-Epoxy-6α-[4-methoxycarbonyl-2-pyridyl]oxy-3-methoxymethoxy-17-methyl-morphin-7-ene

C₂₆ H₂₆ N₂ O₆

MW: 464.52 gmol⁻¹

¹³ C NMR (100 MHz, CDCl₃) δ 165.5, 163.5, 148.3, 147.4, 140.4, 138.9,129.7, 129.1, 128.8, 119.2, 118.5, 116.1, 111.9, 96.0, 88.9, 69.7, 59.1,56.4, 53.4, 46.6, 43.1, 40.9, 35.5, 20.6.

EXAMPLE 42 4,5α-Epoxy-6α-(4-methoxycarbonyl-2-pyridyl)oxy-17-methyl-morphin-7-en-3-ol acetate

C₂₆ H₂₈ N₂ O₇

MW: 480.52 gmol⁻¹

¹³ C NMR (100 MHz, CDCl₃) δ 176.2, 165.4, 163.3, 147.5, 145.8, 140.5,138.8, 130.1, 129.6, 127.8, 124.0, 119.6, 117.2, 116.3, 111.7,88.7,69.6, 59.0, 42.7, 46.4, 42.7, 41.7, 39.0, 34.0, 22.1, 21.2.

EXAMPLE 436α-[5-(Diethylcarbamoyl)-2-pyridyl]oxy-4,5α-epoxy-3-methoxymethoxy-17-methyl-morphin-7-ene

C₂₉ H₃₅ N₃ O₅

MW: 505.62 gmol⁻¹

¹³ C NMR (100 MHz, CDCl₃) δ 168.9, 163.1, 148.2, 145.0, 138.8, 137.7,131.3, 129.2, 128.9, 126.4, 119.1, 118.6, 111.2, 96.1, 89.0, 69.6, 59.0,56.2, 46.6, 43.1, 43.0, 40.8, 35.5, 20.6.

EXAMPLE 446α-[5-(Diethylcarbamoyl)-2-pyridyl]oxy-4,5α-epoxy-17-methyl-morphin-7-en-3-olacetate

C₂₉ H₃₅ N₃ O₆

MW: 521.62 gmol⁻¹

¹³ C NMR (100 MHz, CDCl₃) δ 176.4, 169.3, 163.0, 145.6, 144.8, 139.3,138.0, 130.7, 128.9, 130.7, 128.9, 126.5, 126.3, 122.3, 119.8, 117.6,111.1, 88.1, 68.7, 59.4, 46.7, 41.8, 41.0, 37.8, 32.9, 21.6, 21.4.

EXAMPLE 456α-[6-(Diethylcarbamoyl)-2-pyridyl]oxy-4,5α-epoxy-3-methoxymethoxy-17-methyl-morphin-7-ene

C₂₉ H₃₅ N₃ O₅

MW: 505.62 gmol⁻¹

¹³ C NMR (100 MHz, CDCl₃) δ 168.1, 161.4, 152.3, 148.5, 139.5, 138.8,131.3, 129.7, 129.1, 128.9, 119.1, 118.7, 118.7, 116.6, 112.4, 96.1,89.3, 69.4, 59.0, 56.3, 46.5, 43.2, 43.1, 42.9, 41.1, 39.9, 35.7, 20.6,14., 12.8.

EXAMPLE 466α-[6-(Diethylcarbamoyl)-2-pyridyl]oxy-4,5α-epoxy-17-methyl-morphin-7-en-3-olacetate

C₂₉ H₃₅ N₃ O₆

MW: 521.62 gmol⁻¹

¹³ C NMR (100 MHz, CDCl₃) δ 176.2, 168.1, 161.4, 152.2, 145.8, 139.7,138.7, 129.9, 129.9, 129.8, 128.4, 124.7, 119.5, 117.0, 116.5, 112.2,89.0, 69.3, 58.9, 46.3, 43.0, 42.9, 42.1, 40.0, 39.8, 34.6, 22.3, 20.9,14.4, 12.8.

Example A:

    ______________________________________                                        Haffner test in mice, ED.sub.50 values in nmol/kg, i.v.                                 ED.sub.50 [nmol/kg]                                                 Compound  10 min. 30 min.    60 min.                                                                              120 min.                                  ______________________________________                                        1         2.8     3.3        9.7    17                                          2 1.0 1.4 3.6  6                                                              Morphine.HCl 17 19 21 37                                                    ______________________________________                                    

    ______________________________________                                        Haffner test in mice, ED.sub.50 values in nmol/kg p.o.                                  ED.sub.50 [nmol/kg]                                                 Compound  30 min. 60 min.    120 min.                                                                             180 min.                                  ______________________________________                                        1         54      64         109    170                                         2 22 30  71 113                                                               Morphine.HCl 279  296  539 718                                              ______________________________________                                    

12) Further 7,8-DIHYDROMORPHINE ETHERS CONTAINING A CYCLIC GROUP EXAMPLE1 4,5α-Epoxy-17-methyl-6α-((2-pyridyl)-oxy)-morphinan-7-en-3-ol acetate

4,5α-Epoxy-3-methoxymethoxy-17-methyl-6α-((2-pyridyl)-oxy)-morphinan-7-ene

See Example 1 of "Further ethers" above.

4,5α-Epoxy-3-methoxymethoxy-17-methyl-6α-((2-pyridyl)-oxy)-morphinane

4,5α-Epoxy-3-methoxymethoxy-17-methyl-6α-((2-pyridyl)-oxy)-morphinan-7-ene(1.0 g. 2.46 mmol) is dissolved in MeOH (40 ml), mixed with 10% Pdunactivated charcoal 800 mg and then agitated at RT under H₂ (1 bar overpressure) for 2 hours. The catalyst is eliminated by filtering over afilter compound and a filtrate is concentrated by rotary evaporation.

Yield: 0.94 g (2.3 mmol, 93.5%)

¹³ C NMR (100 MHz, CDCl₃) δ 162.6, 147.5, 146.1, 138.4, 138.0, 129.7,127.0, 118.4, 117.8, 116.1, 111.3, 95.4, 88.2, 68.6, 59.7, 55.8, 46.8,42.3, 41.8, 39.9, 36.1, 24.6, 20.2, 18.9.

4,5α-Epoxy-17-methyl-6α-((2-pyridyl)-oxy)-morphinan-3-ol acetate

4,5α-Epoxy-methoxymethoxy-17-methyl-6α-((2-pyridyl)-oxy)-morphinane(0.940 g, 2.3 mmol) is mixed with H₂ O (35 ml) and glacial acetic acid(35 ml) and stirred for 6 hours at 100° C. The mixture is thenevaporated down at 40° C. using the Rotavapor and the residue obtainedis purified by flash chromatography (90 g silica gel; CH₂ Cl₂/MeOH=4/1). The product is dissolved in H₂ O (7 ml) and glacial aceticacid (0.7 ml) and lyophilised.

Yield: 0.88 g 4,5α-Epoxy-17-methyl-6α-((2-pyridyl)-oxy)-morphinan-3-olacetate (2.07 mnol, 90.1%).

¹³ C NMR (100 MHz, CDCl₃) δ 176.5, 162.8, 146.3, 139.1, 138.8, 128.1,121.6, 119.2, 117.6, 116.8, 111.5, 88.0, 68.5, 60.5, 47.3, 41.1, 40.9,38.3, 34.2, 25.3, 22.1, 21.3, 18.4.

The following were prepared analogously to Example 1

EXAMPLE 24,5α-Epoxy-6α-((5-ethyloxycarbonyl)-2-pyridyl)-oxy)-3-methoxymethoxy-17-methyl-morphinan-3-olacetate

¹³ C NMR (100 MHz, CDCl₃) δ 165.8, 165.5, 149.8, 147.9, 139.6, 139.6,139.5, 129.4, 125.8, 120.1, 119.4, 118.8, 111.2, 95.9, 88.1, 69.8, 61.1,60.9, 56.4, 47.8, 42.4, 41.7, 39.8, 35.5, 25.6, 21.2, 19.0, 14.5.

EXAMPLE 34,5α-Epoxy-6α-((5-ethyloxycarbonyl)-2-pyridyl)-oxy)-17-methyl-morphinan-3-olacetate

¹³ C NMR (100 MHz, CDCl₃) δ 165.3, 165.2, 149.2, 145.3, 139.5, 139.2,127.3, 120.3, 119.7, 119.7, 119.3, 118.0, 110.8, 87.0, 69.1, 61.5, 60.8,50.0, 47.9, 41.0, 40.5, 37.8, 33.3, 25.1, 21.3, 18.0, 14.0.

EXAMPLE 44,5α-Epoxy-3-methoxymethoxy-6α-[21-pyridyl]oxy-17-methyl-morphine

C₂₄ H₂₈ N₂ O₄

MW:408.50 gmol⁻¹

¹³ C NMR (100 MHz, CDCl₃) δ 162.9, 147.8, 146.4, 138.8, 137.4, 130.0,127.3, 118.7, 118.2, 116.5, 111.6, 95.7, 88.5, 68.9, 60.0, 56.1, 47.1,42.7, 42.1, 40.3, 36.4, 24.9, 20.3, 19.2.

EXAMPLE 5 4,5α-Epoxy-6α-[2'pyridyl]oxy-17-methyl-morphin-3-ol acetate

C₂₂ H₂₄ N₂ O₃ AcOH=C₂₄ H₂₈ N₂ O₅

MW:424.50 gmol⁻¹

¹³ C NMR (100 MHz, CDCl₃) δ 176.5, 162.8, 146.3, 145.7, 139.1, 138.8,128.1, 121.6, 119.2, 117.6, 116.8, 111.5, 88.0, 68.5, 47.3, 41.1, 40.9,38.3, 34.2, 25.3, 22.1, 21.3, 18.4.

EXAMPLE 64,5α-Epoxy-3-methoxymethoxy-6α-[2'pyridyl]oxy-17-methyl-morphin

C₂₇ H₃₂ N₂ O₆

MW:480.57 gmol⁻¹

¹³ C NMR (100 MHz, CDCl₃) δ 165.4, 165.3, 149.5, 147.5, 139.3, 139.2,129.1, 125.4, 119.8, 119.0, 118.5, 110.9, 95.6, 87.8, 69.4, 60.8, 60.6,56.1, 47.5, 42.0, 41.4, 19.4, 35.1, 25.3, 20.9, 18.7, 14.2.

EXAMPLE 7 4,5α-Epoxy-6α-[2pyridyl]oxy-17-methyl-morphin-3-ol acetate

C₂₅ H₂₈ N₂ O₅ AcOH=C₂₇ H₃₂ N₂ O₇

MW:496.57 gmol⁻¹

¹³ C NMR (100 MHz, CDCl₃) δ 176.2, 165.5, 165.3, 149.4, 145.4, 139.7,139.0, 128.1, 121.2, 120.0, 119.4, 117.8, 110.9, 87.66, 69.2, 61.0,60.9, 47.6, 41.1, 40.9, 38.3, 33.8, 25.5, 21.8, 21.3, 18.3, 14.3.

EXAMPLE 84,5α-Epoxy-3-methoxymethoxy-6α-[2-pyrazinyl]oxy-17-methyl-morphine

C₂₃ H₂₇ N₃ O₄

MW:409.48 gmol⁻¹

¹³ C NMR (100 MHz, CDCl₃) δ 159.5, 147.3, 140.0, 138.9, 136.3, 136.2,130.0, 119.0, 117.6, 95.6, 88.3, 69.8, 59.8, 56.1., 47.2, 42.9, 42.3,41.3, 36.7, 29.7, 25.6, 20.3, 19.2.

EXAMPLE 9 4,5α-Epoxy-6α-[2-pyrazinyl]oxy-17-methyl-morphin-3-ol acetate

C₂₃ H₂₇ N₃ O₅

MW:425.48 gmol⁻¹

¹³ C NMR (100 MHz, CDCl₃) δ 176.5, 159.6, 145.5, 140.4, 139.2, 135.9,135.6, 128.3, 122.1, 119.3, 117.6, 87.7, 69.6, 60.1, 47.1, 41.3, 41.2,38.9, 34.5, 25.6, 22.3, 21.0, 18.5.

EXAMPLE 106α-[2-Quinolinyl]oxy-4,5α-epoxy-3-methoxymethoxy-17-methyl-morphin

C₂₈ H₃₀ N₂ O₄

MW:458.54 gmol⁻¹

¹³ C NMR (100 MHz, CDCl₃) δ 161.2, 148.0, 146.3, 138.7, 138.4, 130.3,129.3, 127.3, 125.1, 123.8, 118.8, 118.2, 113.6, 95.8, 88.5, 69.2, 60.0,47.1, 42.9, 42.4, 40.4, 36.8, 24.6, 20.4, 19.5.

EXAMPLE 11 6α-[2-Quinolinyl]oxy-4,5α-epoxy-17-methyl-morphin-3-olacetate

C₂₈ H₃₀ N₂ O₅

MW:474.54 gmol⁻¹

¹³ C NMR (100 MHz, CDCl₃) δ 176.7, 161.0, 146.1, 145.9, 139.3, 138.7,129.4, 128.0, 127.3, 127.0, 125.1, 123.9, 121.3, 119.2, 117.7, 113.3,87.7, 68.4, 60.3, 47.1, 40.9, 40.7, 38.2, 34.1, 25.2, 22.2, 21.2, 18.4.

EXAMPLE :124,5α-Epoxy-3-methoxymethoxy-17-methyl-6α-[2-pyrimidinyl]oxy-morphine

C₂₃ H₂₇ N₃ O₄

MW:409.48 gmol⁻¹

¹³ C NMR (100 MHz, CDCl₃) δ 164.7, 158.8, 147.4, 138.9, 129.9, 128.9,128.2, 119.1, 117.9, 114.6, 95.9, 88.2, 71.0, 59.8, 56.0, 46.9, 43.0,42.6, 37.1, 25.2, 20.3, 19.6.

EXAMPLE 13 4,5α-Epoxy-17-methyl-6α-[2-pyrimidinyl]oxy-morphin-3-olacetate

C₂₃ H₂₇ N₃ O₅

MW:425.48 gmol⁻¹

¹³ C NMR (100 MHz, CDCl₃) δ 176.6, 164.3, 159.0, 145.4, 139.2, 128.0,122.4, 119.4, 117.8, 114.9, 87.5, 70.9, 60.1, 46.7, 41.8, 41.2, 37.4,34.8, 24.2, 22.4, 21.1, 19.1.

Pharmacological Examples:

    ______________________________________                                        Haffner test in mice, ED.sub.50 values in nmol/kg, i.v.                                  ED.sub.50 [nmol/kg]                                                Compound   10 min. 30 min.   60 min.                                                                              120 min.                                  ______________________________________                                        1          3.5     3.8       9.6    19                                          2 1.2 1.8 3.8  8                                                              7,8-Dihydro- 16 23 32 130                                                     morphine.AcOH                                                                 Morphine.HCl 17 19 21 37                                                    ______________________________________                                    

    ______________________________________                                        Haffner test in mice, ED.sub.50 values in nmol/kg, p.o.                                  ED.sub.50 [nmol/kg]                                                Compound   30 min. 60 min.   120 min.                                                                             180 min.                                  ______________________________________                                        1           51      60       113    200                                         3  26  30  72 132                                                             7,8-Dihydro- 177 195 250 481                                                  morphine.AcOH                                                                 Morphine.HCl 279 296 539 718                                                ______________________________________                                    

What is claimed is:
 1. A morphinan derivative of the formula ##STR6##wherein D denotes a straight-chained or branched, optionally halogenatedC₁₋₄ -alkyl group,the dotted line represent a chemical bond indicatingthat the compound is a morphine or 7,8-dihydromorphine derivative, Pdenotes a group --C(L) (R₁) (R₂), L denotes a group --A₁ --(C(R₃)(R₄))_(k) --A₂ --B k is an integer from 0 to 5; R₁, R₂, R₃ and R₄independently of one another denote hydrogen, a straight-chained orbranched, C₁₋₄ -alkyl group, a C₂₋₄ -alkenyl group, or a group--(CH₂)_(x) --OR₇, --(CH₂)_(x) --OC(O)R₇, (CH₂)_(x) --F, (CH₂)_(x) --Cl,(CHF)_(x) --F, (CHCl)_(x) --Cl, (CF₂)_(x) --F, (CCl₂)_(x) --Cl, x is aninteger from 0 to 2, A₁ and A₂ independently of each other denote agroup --(CH₂)_(m) --, m is an integer from 0 to 4, B is a hydrogen atomor a group X, and X denotes a group --(CH₂)_(n) --OH, --(CH₂)_(n) --CO₂R₇, --(CH₂)_(n) --CN, --(CH₂)_(n) --CONR₅ OR₆, --(CH₂)_(n) CONR₅ R₆,--(CH₂)_(n) --OR₅, --(CH₂)_(n) --COR₅, --(CH₂)_(n) --OC(O)R₇,--(CH₂)_(n) --CONR₅ OR₆, --(CH₂ O_(n) --NR₅ C(O)R₆, --(CH₂)_(n) --SR₅,--(CH₂)_(n) S(O)R₅, --(CH₂)_(n) --S(O)₂ NR₅ R₆, --(CH₂)_(n) --NR₅ R₆,--(CH₂)_(n) --NHC(O)R₅, --(CH₂)_(n) --NHS(O)₂ R₅, --(CH₂)_(n) --F,--(CH₂)_(n) --Cl, --(CH₂)_(n) --Br, --(CH₂)_(n) --NO₂ n is an integerfrom 0 to 4, R₅, R₆ and R₇ independently of one another denote hydrogenor a straight-chained or branched C₁₋₄ -alkyl group, a C₂₋₄ -alkenylgroup or an aryl or benzyl group, or a pharmaceutically acceptable saltthereof.
 2. A pharmaceutical preparation containing a compound offormula I according to claim 1 or a pharmaceutically acceptable saltthereof, in admixture with a pharmaceutically acceptable carrier,diluent or excipient.
 3. A morphinan derivative according to claim 1which is4,5α-epoxy-6α((4-hydroxy-butyl)-oxy)-17-methyl-morphinan-7-en-3-olacetate.
 4. A pharmaceutical composition comprising a compound offormula I according to claim 1 or a pharmaceutically acceptable saltthereof, in admixture with a pharmaceutically acceptable carrier,diluent or excipient.
 5. A composition of claim 4 which is an analgesiccomposition.
 6. A method for alleviating pain which comprisesadministering an effective amount of the compound in claim 3 to apatient in need thereof.
 7. A morphinan derivative of formula Iaccording to claim 1, wherein D denotes a methyl group.
 8. A method foralleviating pain which comprises administering an effective amount ofthe composition of claim 6 to a patient in need thereof.
 9. A method foralleviating pain which comprises administering an effective amount ofthe compound in claim 1 to a patient in need thereof.